Amyloid-β deposition in mild cognitive impairment is associated with increased hippocampal activity, atrophy and clinical progression

Abstract

Cross-sectional functional magnetic resonance imaging studies using a memory task in patients with mild cognitive impairment have produced discordant results, with some studies reporting increased hippocampal activity--consistent with findings in genetic at-risk populations--and other studies reporting decreased hippocampal activity, relative to normal controls. However, previous studies in mild cognitive impairment have not included markers of amyloid-β, which may be particularly important in prediction of progression along the Alzheimer's disease continuum. Here, we examine the contribution of amyloid-β deposition to cross-sectional and longitudinal measures of hippocampal functional magnetic resonance imaging activity, hippocampal volume, global cognition and clinical progression over 36 months in 33 patients with mild cognitive impairment. Amyloid-β status was examined with positron emission tomography imaging using Pittsburg compound-B, hippocampal functional magnetic resonance imaging activity was assessed using an associative face-name memory encoding task, and hippocampal volume was quantified with structural magnetic resonance imaging. Finally global cognition was assessed using the Mini-Mental State Examination and clinical progression was assessed using the Clinical Dementia Rating (Sum of Boxes). At baseline, amyloid-β positive patients with mild cognitive impairment showed increased hippocampal activation, smaller hippocampal volumes, and a trend towards lower Mini-Mental State Examination scores and higher Clinical Dementia Ratings compared to amyloid-β negative patients with mild cognitive impairment. Longitudinally, amyloid-β positive patients with mild cognitive impairment continued to show high levels of hippocampal activity, despite increasing rates of hippocampal atrophy, decline on the Mini-Mental State Examination and faster progression on the Clinical Dementia Ratings. When entered simultaneously into the same linear mixed model, amyloid-β status, hippocampal activation, and hippocampal volume independently predicted clinical progression. These results indicate that amyloid-β positive patients with mild cognitive impairment are more likely on a path towards Alzheimer's disease dementia than amyloid-β negative patients. Increased hippocampal activity is discussed in relation to neuronal compensation and/or amyloid-β induced excitoxicity.

Keywords: MCI; amyloid deposition; clinical progression; functional MRI; hippocampal activation.

© The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Figures

Figure 1

Schematic representation of data collected in patients with mild cognitive impairment. From top to bottom: (1) Functional MRI (fMRI) collected during an associative face-name encoding task; (2) hippocampal volume (HV), (3) Mini-Mental State Examination (MMSE) and Clinical Dementia Rating Sum of Boxes score (CDRSB); and (4) amyloid-β PET imaging (Aβ). Functional MRI: shows brain activity depicted in yellow/red projected on an inflated brain for right hemisphere, midline and a sagittal slice with the hippocampus, shown at P < 0.001 (uncorrected) from the contrast novel-repeated at baseline (BL), 3, 6, 12, 18, 24 and 36 months (m). Hippocampal volume: shows the anatomical T1-weighted scans of one MCI patient, analysed with the longitudinal FreeSurfer pipeline and used to estimate grey matter volume of the hippocampus (shown in yellow). MMSE/CDRSB: shows time points of neuropsychological examination matched to the closest MRI visit. Amyloid-β: shows an example of an Aβ+ PET scan, using PiB. PET data acquisition was collected near baseline (4 months) and used to identify Aβ− and Aβ+ patients with MCI. Below each visit number of observations (n) are shown in grey for at each visit separately for functional MRI, hippocampal volume, CDRSB and the amyloid-β PET scans.

Figure 2

Baseline results. (A) A scatter plot of PiB retention values at baseline. The y-axis contains the neocortical PiB retention values, normalized by a DVR. The black line indicates the 1.20 cut-off used to classify Aβ+ and Aβ− MCIs. (B) Baseline functional MRI (fMRI) activity. The y-axis contains the average beta-estimate from both left and right hippocampus. (C) Average baseline hippocampal volume (HV). The y-axis contains the total hippocampal volume in mm3 of both left and right hippocampus. (D) Baseline Mini-Mental State Examination scores (MMSE). (E) Baseline Clinical Dementia Rating Sum of Boxes scores (CDRSB). The Aβ− MCI group is shown in blue and Aβ+ MCI in red. Error bars denote the standard error of the mean.

Figure 3

Longitudinal results. (A) Estimates from linear mixed models in functional MRI (fMRI) activity. The y-axis contains the average beta-estimates from both left and right hippocampus. (B) Estimates in hippocampal volume (HV). The y-axis contains total hippocampal volume in mm3 of both left and right hippocampus. (C) Estimates in Mini-Mental State Examination (MMSE), with lower scores representing lower cognition. (D) Estimates in Clinical Dementia Rating Sum of Boxes score (CDRSB), with higher score representing greater clinical deficits. The x-axis shows time in months. The Aβ− MCI group is shown in blue and Aβ+ MCI in red. Grey area denotes the standard error of the mean.