Altered excitatory and inhibitory neuronal subpopulation parameters are distinctly associated with tau and amyloid in Alzheimer’s disease

Abstract

Background: Neuronal and circuit level abnormalities of excitation and inhibition are shown to be associated with tau and amyloid-beta (Aβ) in preclinical models of Alzheimer's disease (AD). These relationships remain poorly understood in patients with AD.Methods: Using empirical spectra from magnetoencephalography (MEG) and computational modeling (neural mass model; NMM) we examined excitatory and inhibitory parameters of neuronal subpopulations and investigated their specific associations to regional tau and Aβ, measured by positron emission tomography (PET), in patients with AD.Results: Patients with AD showed abnormal excitatory and inhibitory time-constants and neural gains compared to age-matched controls. Increased excitatory time-constants distinctly correlated with higher tau depositions while increased inhibitory time-constants distinctly correlated with higher Aβ depositions.Conclusions: Our results provide critical insights about potential mechanistic links between abnormal neural oscillations and cellular correlates of impaired excitatory and inhibitory synaptic functions associated with tau and Aβ in patients with AD.Funding: This study was supported by the National Institutes of Health grants: K08AG058749 (KGR), F32AG050434-01A1 (KGR), K23 AG038357 (KAV), P50 AG023501, P01 AG19724 (BLM), P50-AG023501 (BLM & GDR), R01 AG045611 (GDR); AG034570, AG062542 (WJ); NS100440 (SSN), DC176960 (SSN), DC017091 (SSN), AG062196 (SSN); a grant from John Douglas French Alzheimer's Foundation (KAV); grants from Larry L. Hillblom Foundation: 2015-A-034-FEL and (KGR); 2019-A-013-SUP (KGR); a grant from the Alzheimer's Association: (PCTRB-13-288476) (KAV), and made possible by Part the CloudTM, (ETAC-09-133596); a grant from Tau Consortium (GDR & WJJ), and a gift from the S. D. Bechtel Jr. Foundation.

Altered low-frequency brain rhythms precede changes in gamma power during tauopathy

“…Our results are consistent with previous recordings in dorsal entorhinal cortex, which showed reduced power at gamma frequencies in 7- to 8-month-old Tau+ rTg4510 animals ( Booth et al., 2016a ). As previous works suggest there are no changes in the number of inhibitory neurons in Tau+ rTg4510 animals ( Booth et al., 2016a ; Shimojo et al., 2020 ), the reduced gamma may instead reflect changes in GABAergic synapses, sub-classes of inhibitory neurons, or the balance of excitation and inhibition in cortical networks ( Fu et al., 2019 ; Maestu et al., 2021 ; Ranasinghe et al., 2022 ; Shimojo et al., 2020 ). Our observations further show little effect of tauopathy on gamma at 5 months of age, suggesting that earlier stages of synaptic dysfunction (before the onset of degeneration) have limited effect on the interneuron networks which are hypothesized to be responsible for gamma rhythms.…”

“…EEG measurements in human patients with AD show that the power of low-frequency oscillations is increased in dementia ( Coben et al., 1983 ; Huang et al., 2000 ; Ranasinghe et al., 2022 ), and that these changes are more prominent during resting states ( Babiloni et al., 2009 ; de Haan et al., 2008 ). The gamma activity that normally accompanies visual stimulation is also impaired in patients with mild cognitive impairment or AD ( Murty et al., 2021 ).…”

Whole-brain modeling explains the context-dependent effects of cholinergic neuromodulation

“…We are aware of the potential of personalized whole-brain models for characterizing brain dynamics [95]. They can be used in clinical and translational neuroscience to propose model-inspired therapies, at the single subject level, with the aim to restore the normal brain function, and also to establish causal links between the model mechanisms (e.g., biophysical parameters fitted for individual patients) and the functional disturbances or cognitive decline ascribed to brain disorders [105,106]. In spite of this, we believe that using individual whole-brain models might be not necessary for finding global principles of how context-dependent effects of cholinergic neuromodulation influence the functional network topology of the brain, as explored in our work.…”

Structure-function models of temporal, spatial, and spectral characteristics of non-invasive whole brain functional imaging

“…In the latter, we also outlined a strategy to capture temporal fluctuations in MEG by fitting the SGM parameters to MEG frequency spectra at various time points. The mesoscopic SGM model parameters were also estimated to differentiate Alzheimer's disease with healthy controls (Ranasinghe et al, 2022 ), as well as different stages of sleep (Fan et al, 2022 ).…”

“…The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/ fnins. 2022…”