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.

Paradoxical fMRI overconnectivity upon chemogenetic silencing of the prefrontal cortex

“…EEG and MEG studies in patients with stroke or neurodegenerative brain disorders lend indirect support to this hypothesis, as both rsfMRI overconnectivity and robust δ hyper-synchronization have been observed ipsilaterally to lesioned areas in stroke 20,49 . Similar findings have been reported in Alzheimer's disease patients, in which this effect appears to be especially prominent in polymodal cortical areas 50,51 . Within such a framework, functional impairments in cortical activity following degenerative pathology could manifest as hyper-synchronization during pre-disease states, eventually reverting to hypotrophy-associated under-connectivity at advanced stages of brain pathology.…”

In vivo tau pathology is associated with synaptic loss and altered synaptic function

“…These associations should therefore be interpreted with caution. However, recent findings by Ranasinghe and colleagues do suggest that the frontal delta band may contain clinically relevant information regarding the role of tau pathology in Alzheimer's disease [49].…”

“…Ranasinghe and colleagues evaluated the association between [ 18 F]flortaucipir PET and an MEG measure of functional connectivity between neuronal populations [49]. Direct comparisons should be made with caution, as in our study we used spectral measures within neuronal populations (i.e.…”

“…Finally, to explore whether each imaging modality was associated with cognition, we performed Spearman correlation analyses between MMSE and average [ 18 F]flortaucipir BP ND , [ 11 C]UCB-J BP ND and MEG spectral measures. We selected relative alpha power based on previous work [49]. Additionally, we added absolute broadband power as it contains all frequency bands.…”

Cortical silencing results in paradoxical fMRI overconnectivity

“…Our findings offer an alternative network-level mechanism for these clinical observations, suggesting that rsfMRI overconnectivity may reflect shifts in the balance between the amount of interareal synchronization due to direct axonal communication and low-frequency brainwide synchronization mediated by single centers such as the polymodal thalamus (Gent et al, 2018) or by neuromodulatory nuclei (Safaai et al, 2015;Reimann and Niendorf, 2020), a conceivable scenario in early-stage degenerative or neurological states characterized by loss of neuronal function in higher order cortical areas. MEG and EEG studies in neurodegenerative brain disorders provide indirect support to this hypothesis, as evidence of robust δ hyper-synchronicity in Alzheimer's disease patients has been repeatedly reported, an effect that appears to preferentially involve polymodal cortical areas (Huth et al, 2012;Ranasinghe et al, 2020). Within such a framework, functional impairments in cortical activity following degenerative pathology could manifest as hypersynchronization during predisease states, eventually reverting to hypotrophy-associated underconnectivity at advanced stages of brain pathology.…”