Electromagnetic signatures of the preclinical and prodromal stages of Alzheimer's disease

Abstract

Biomarkers useful for the predementia stages of Alzheimer's disease are needed. Electroencephalography and magnetoencephalography (MEG) are expected to provide potential biomarker candidates for evaluating the predementia stages of Alzheimer's disease. However, the physiological relevance of EEG/MEG signal changes and their role in pathophysiological processes such as amyloid-β deposition and neurodegeneration need to be elucidated. We evaluated 28 individuals with mild cognitive impairment and 38 cognitively normal individuals, all of whom were further classified into amyloid-β-positive mild cognitive impairment (n = 17, mean age 74.7 ± 5.4 years, nine males), amyloid-β-negative mild cognitive impairment (n = 11, mean age 73.8 ± 8.8 years, eight males), amyloid-β-positive cognitively normal (n = 13, mean age 71.8 ± 4.4 years, seven males), and amyloid-β-negative cognitively normal (n = 25, mean age 72.5 ± 3.4 years, 11 males) individuals using Pittsburgh compound B-PET. We measured resting state MEG for 5 min with the eyes closed, and investigated regional spectral patterns of MEG signals using atlas-based region of interest analysis. Then, the relevance of the regional spectral patterns and their associations with pathophysiological backgrounds were analysed by integrating information from Pittsburgh compound B-PET, fluorodeoxyglucose-PET, structural MRI, and cognitive tests. The results demonstrated that regional spectral patterns of resting state activity could be separated into several types of MEG signatures as follows: (i) the effects of amyloid-β deposition were expressed as the alpha band power augmentation in medial frontal areas; (ii) the delta band power increase in the same region was associated with disease progression within the Alzheimer's disease continuum and was correlated with entorhinal atrophy and an Alzheimer's disease-like regional decrease in glucose metabolism; and (iii) the global theta power augmentation, which was previously considered to be an Alzheimer's disease-related EEG/MEG signature, was associated with general cognitive decline and hippocampal atrophy, but was not specific to Alzheimer's disease because these changes could be observed in the absence of amyloid-β deposition. The results suggest that these MEG signatures may be useful as unique biomarkers for the predementia stages of Alzheimer's disease.

Figure 1

General profiles of the power spectra at each region of interest. (A) Waveforms of the power spectra for each group and their two-way subtractions (amyloid-β-positive groups − amyloid-β-negative groups, and MCI groups − CN groups). Brain images show the shape of the regions of interest. ACC = anterior cingulate cortex; FMC = frontal medial cortex; LFC and RFC = left and right frontal cortices; LIPL and RIPL = left and right inferior parietal lobules; LTC and RTC = left and right temporal cortices; OC = occipital cortex; PCu/PCC = precuneus/posterior cingulate cortex; see also Supplementary Table 1. (B) F-values for the main effects of amyloid-β deposition and clinical status and their interactions, plotted by frequency. The F-values were adjusted for the effects of age. Each region of interest profile is coded in a different colour. (C) F-values for the group-wise comparisons.

Figure 2

MEG power markers representing the effects of amyloid-β (Aβ) deposition and clinical status. The shape of each cluster is overlapped on the standard brain of the Montreal Neurological Institute. Each arrow indicates the peak frequency where the maximum effect was detected. The red colour indicates that the amyloid-β-positive groups showed larger power than the amyloid-β-negative groups, the green colour indicates larger power in the MCI groups than the CN groups, and the blue colour indicates the opposite.

Figure 3

Relationships between the relative MEG power and regional amyloid-β deposition. Top: Scatter plots of the power marker values with local PiB-SUVR values, which were computed when limited within each power marker cluster, within the CN groups (left), and within the MCI groups (right). Closed circles indicate amyloid-β-positive individuals, and open circles indicate amyloid-β-negative individuals. Partial r-values represent correlation coefficients adjusted for the effects of age. The partial r-value was also computed by restricting the values within the amyloid-β-positive group for each CNp and MCIp. Middle: Whole-brain multiple regression analysis between PiB-PET SUVR images and power marker values adjusted for the effects of age. Significant clusters (FWE-corrected P < 0.05 at a height threshold of P = 0.001) are displayed. Bottom: Overlays of the cluster shape of MEG power markers (red) and significant regions detected in the above regression analyses (yellow). Overlapped areas are shown in orange.

Figure 4

Multiple regression analysis between the power marker values and regional grey matter volume (A–C) or regional glucose metabolism (D), adjusting for the effects of age. (A) Results of multiple regression analysis using whole-brain voxel-based morphometry (VBM) for power markers that represent the main effects of clinical category in all subjects (n = 66). Left: Delta power at 2.5 Hz in the posterior part of the brain. Right: Theta power at 4.5 Hz in the global brain. Regions in which the grey matter volumes showed significant negative correlations (FWE-corrected P < 0.05 at a height threshold of P = 0.001, adjusted for the effects of age) were visualized. (B) Results of VBM for the power markers that represent the effects of clinical category within the amyloid-β-negative groups (CNn and MCIn, n = 28). Left: Delta power at 2.5 Hz in the occipitotemporal areas (FWE-corrected P < 0.05 at a height threshold of P = 0.001). Right: Theta power at 4.5 Hz in the occipitotemporal areas (FWE-corrected P < 0.05 at a height threshold of P = 0.005). (C) Results of VBM analyses for power markers that represent the effects of clinical category within the amyloid-β-positive groups (CNp and MCIp, n = 38) as 3.5-Hz delta power in the medial prefrontal areas (FWE-corrected P < 0.05 at a height threshold of P = 0.005). (D) Results of multiple regression analysis of FDG-PET images in the amyloid-β-positive groups (CNp and MCIp, n = 38) for the same power marker as C. Statistically significant clusters in which regional glucose metabolism showed significant negative correlations with the power marker values are visualized (FWE-corrected P < 0.05 at a height threshold of P = 0.001). sMRI = structural MRI.

Figure 5

A schematic summarizing the main findings. The left and right red arrows and their connected boxes demonstrate the characteristics of the MEG power markers that represented the effects of amyloid-β deposition within the CN groups and within the MCI groups, respectively. The upper and lower red arrows and their connected boxes demonstrate the characteristics of the MEG power markers that represented the effects of clinical category within the amyloid-β-positive groups and within the amyloid-β-negative groups, respectively. The arrows with the gradation colours indicate the directions where the relative power increases (not indicating clinical transition).