The pathophysiological features of Alzheimer’s Disease are broadly consistent (e.g. extracellular deposition of amyloid beta 1-42 and intracellular accumulation of phospho-tau), but the clinical phenotype is heterogeneous with different manifestations of the symptoms over time. Several structural, molecular, and functional neuroimaging markers capture several important underlying structural and functional cortical and subcortical abnormalities. However, they cannot explore a potentially critical angle of the Alzheimer’s disease as a pathology of distributed cognitive systems, namely the neurophysiological mechanisms of neural synchronization and coupling in the complex linear and nonlinear interactions of neurons and distributed neural populations at millisecond time scale. This Session will highlight new findings obtained from neurophysiological methods to study those interactions in neuronal circuitry and signal transmission at spatial macro-, meso-, and micro-scale, conferred by Alzheimer’s disease specific pathologies in living systems. Furthermore, the Session will focus on the issue of translation (from preclinical to clinical) vs. back-translation (from clinical to preclinical) of electrophysiology biomarkers in research and drug discovery and development. Finally, findings on the cross-modal validity and specificity of the electrophysiological markers of Alzheimer’s disease will be presented and discussed.

A tau seeding model was used wherein pre-formed synthetic tau fibrils (K18) are unilaterally injected into either the hippocampus or the locus coeruleus (LC) of a transgenic mouse model of Alzheimer’s Disease (AD), which expresses mutant human P301L tau.After hippocampal K18-injections, network alterations and clear theta–gamma EEG uncoupling in a hippocampal network were detected before Tau pathology and neuronal loss. Specifically, there was a decreased intra- and inter-hemispheric hippocampal theta directionality and functional phase-amplitude theta-gamma coupling strength. These findings support the view that disruptions in synaptic plasticity and progressive loss of functional connectivity in the hippocampus are hypothesized to underlie cognitive deficits.

<p>In the European IMI PharmaCog project (Grant Agreement n&deg;115009, www.pharmacog.org), we evaluated the hypothesis that resting state electroencephalographic (rsEEG) and auditory oddball ERP/markers may be sensitive to transient experimental challenges of cognitive performance in young volunteers (Healthy) for future applications to very early drug discovery phases. Cortical sources of delta and alpha rsEEG rhythms and auditory oddball P3b of ERPs were abnormal in mild cognitive impairment patients positive to cerebrospinal markers of Alzheimer&rsquo;s disease (MCI+) compared with MCI- subjects. Furthermore, one-night sleep deprivation (SD) altered the cognitive performance as well as cortical sources of delta and alpha rsEEG rhythms and auditory oddball P3b peak in Healthy subjects, while Modafinil partially recovered them. These rsEEG and auditory ERP markers can be back-translated from prodromal Alzheimer&rsquo;s disease patients to healthy young volunteers under a cognitive challenge (e.g. SD).</p>

The differential diagnosis of Alzheimer's disease (AD) and Dementia with Lewy bodies (DLB) is challenging. Enriching the biomarkers for this diagnosis, we underwent 72 participants (21 Controls, 30 AD, 21 DLB) to rsEEG and 3 T MR imaging. MRI index was derived from medial temporal atrophy (MTA) ratings. A mixed rsEEG-MRI model showed the best classification accuracy of 93% for AD and 86% for DLB. It was concluded that multimodal rsEEG-MRI approaches might be advantageous, especially in settings where neuroimaging of dopaminergic system is not available.