Neurophysiological signatures in Alzheimer's disease are distinctly associated with TAU, amyloid-β accumulation, and cognitive decline

Abstract

Neural synchrony is intricately balanced in the normal resting brain but becomes altered in Alzheimer's disease (AD). To determine the neurophysiological manifestations associated with molecular biomarkers of AD neuropathology, in patients with AD, we used magnetoencephalographic imaging (MEGI) and positron emission tomography with amyloid-beta (Aβ) and TAU tracers. We found that alpha oscillations (8 to 12 Hz) were hyposynchronous in occipital and posterior temporoparietal cortices, whereas delta-theta oscillations (2 to 8 Hz) were hypersynchronous in frontal and anterior temporoparietal cortices, in patients with AD compared to age-matched controls. Regional patterns of alpha hyposynchrony were unique in each neurobehavioral phenotype of AD, whereas the regional patterns of delta-theta hypersynchrony were similar across the phenotypes. Alpha hyposynchrony strongly colocalized with TAU deposition and was modulated by the degree of TAU tracer uptake. In contrast, delta-theta hypersynchrony colocalized with both TAU and Aβ depositions and was modulated by both TAU and Aβ tracer uptake. Furthermore, alpha hyposynchrony but not delta-theta hypersynchrony was correlated with the degree of global cognitive dysfunction in patients with AD. The current study demonstrates frequency-specific neurophysiological signatures of AD pathophysiology and suggests that neurophysiological measures from MEGI are sensitive indices of network disruptions mediated by TAU and Aβ and associated cognitive decline. These findings facilitate the pursuit of novel therapeutic approaches toward normalizing network synchrony in AD.

Fig. 1.. Resting-state neural synchronizations in patients with AD compared with age-matched controls.

Each brain rendering depicts the t maps from the voxel-wise comparison of global imaginary coherence between groups for alpha (A) and delta-theta (B) oscillations. Cold colors indicate hyposynchrony, and hot colors indicate hypersynchrony. The color maps are thresholded with a cluster correction of 25 voxels (P < 0.01) and at 5% FDR (n = 60, patients with AD; n = 20, age-matched controls).

Fig. 2.. Resting-state neural synchronizations in each neurobehavioral phenotype of AD compared with age-matched controls.

Each row represents the three AD phenotypes, from top to bottom, AD-amnestic/dysexecutive (AD-AMN), logopenic variant of primary progressive aphasia (AD-lvPPA), and posterior cortical atrophy (AD-PCA). The left column (A) shows the alpha synchrony, and the right column (B) shows the delta-theta synchrony, in each AD phenotype when compared with age-matched controls. Cold colors indicate hyposynchrony, and hot colors indicate hypersynchrony. The brain renderings depict the t maps from the voxel-wise comparison of global imaginary coherence. The color maps are thresholded with a cluster correction of 25 voxels (P < 0.01) at 5% FDR (n = 30, 15, 15, and 20 for AD-AMN, AD-lvPPA, AD-PCA, and age-matched controls, respectively).

Fig. 3.. Spatial colocalization between neuronal synchrony and flortaucipir and ¹¹C-PIB uptakes.

Images show the voxel-wise Gwet’s Agreement coefficient (Gwet’s AC) between alpha hyposynchrony and flortaucipir uptake (A), between delta-theta hypersynchrony and flortaucipir uptake (B), between alpha hyposynchrony and ¹¹C-PIB uptake (C), and between delta-theta hypersynchrony and ¹¹C-PIB uptake (D). Images are thresholded to show Gwet’s AC scores depicting high agreement (>0.5; depicted in yellow-orange color scheme) or high disagreement (<−0.5; depicted in blue color scheme) [n = 12 patients included in the analyses for subplots (A) and (B); n = 18 patients included in the analyses for subplots (C) and (D)].

Fig. 4.. Functional associations between neural synchronization deficits and the degree of Aβ and TAU depositions.

Contour plots depict the main effects and interactive effects of flortaucipir (TAU) uptake and ¹¹C-PIB (Aβ) uptake on alpha (left subplot) and delta-theta (right subplot) synchrony abnormalities in a voxel-wise general linear model based on subjects scanned with all three modalities of imaging: MEGI; flortaucipir; ¹¹C-PIB PET. X axes represent the degree of ¹¹C-PIB uptake (DVR), and Y axes represent the degree of flortaucipir uptake (SUVR). Color gradients represent the degree of neuronal synchrony represented as Z scores (depicted in contour lines), where blue represents reduced neuronal synchrony (hyposynchrony) and red represents increased neuronal synchrony (hypersynchrony), based on age-matched normal controls. (n = 12 patients with AD).

Fig. 5.. Alpha synchronizations demonstrate associations with global cognitive decline in patients with AD.

Alpha (A) and delta-theta (B) synchrony is plotted against Mini Mental State Exam (MMSE) scores in patients with AD. The X axes show the four quartiles of MMSE. The plots depict the least square means corrected for age and sex, and the SEs, derived from the mixed model analysis. Y axes depict the frequency-specific neuronal synchrony values derived as global imaginary coherence (see Materials and Methods) for alpha and delta-theta bands (n = 26 patients with AD with MMSE evaluation within 30 days of MEGI). MMSE scores range from 0 to 30, with higher scores denoting better cognitive function.