Neuronal hyperexcitability in AD

Abstract

AbstractBackgroundBecause neuronal and network deficits are the imperative immediate consequences of pathological changes of disease mechanisms, neurophysiological manifestations associated with Aβ and tau are uniquely positioned to demonstrate the abnormal homeostatic and maladaptive circuit alterations and the dynamic integrated effects of underlying genetics and neuropathological changes in Alzheimer’s disease (AD). Importantly, network dysfunction manifesting as abnormal hyper‐ as well as hypo‐active oscillatory brain rhythms is detectable even during the prodromal phase of disease. Here we leveraged the higher spatial and precise temporal resolution of Magnetoencephalography (MEG) to define frequency‐specific and region‐dependent patterns of oscillatory deficits in AD patients, and to demonstrate the earliest neurophysiological abnormalities associated with AD neuropathology and their mechanistic relationships to network hyperexcitability.MethodWe studied the resting brain oscillations in individuals with AD‐spectrum (n = 88) and age‐matched controls (n = 70) using MEG. In addition, subsets of participants were evaluated with positron emission tomography (PET) with Aβ and tau specific tracers and fluid biomarker including plasma P‐tau181 and Neuro‐Filament‐Light (NFL). We used statistical mixed models to investigate the associations between neural oscillations and pathology. We used a linear Neural‐Mass‐Model (NMM) in combination with empirical MEG spectra to derive the excitatory‐to‐inhibitory activity within neuronal subpopulations in AD patients. Based on standard neurophysiological monitoring we determined clinical evidence of hyperexcitability as AD with and without epileptiform activity (AD‐EPI+; AD‐EPI‐).ResultWhile increase and decrease of oscillatory activity are distinctly associated Aβ and tau, respectively, the characteristic frequency‐specific manifestation in AD was increased spectral signature within delta‐theta (2‐7Hz) and reduced spectral signature within alpha (8‐12Hz). Earliest spectral changes were detected in Aβ+ cognitively unimpaired and the increased spectral signature associated with Aβ was replicated in identical associations with plasma p‐tau181. The presence of APO‐E4 allele strengthened these associations. NMM demonstrated greater excitatory‐inhibitory‐activity in AD‐EPI+ vs. AD‐EPI‐ while these were specifically correlated with the reduced alpha spectrum which was more profound in AD‐EPI+ as well as uniquely associated with increased tau depositions.ConclusionOur 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.