Dottorato in NEUROSCIENZE CLINICO-SPERIMENTALI E PSICHIATRIA

Titolo della tesi: Abnormal Delta EEG Cortical Sources As A Neurophysiological Biomarker Of Vigilance Dysfunctions In Patients With Mild Cognitive Impairment Due To Alzheimer’s Disease

Alzheimer’s disease (AD), the most common neurodegenerative condition, is characterized by a progressive cognitive decline that classically begins with episodic memory loss, later encompassing numerous cognitive domains. AD signs and symptoms are secondary to deposition of its hallmark neuropathological features, amyloid-β plaques and neurofibrillary tau tangles. A growing body of evidence is mounting highlighting how disruptions in vigilance, arousal regulation, and sleep-wake rhythms are also important, and often overlooked, features of AD pathophysiology. These non-cognitive symptoms manifest early, often preceding overt cognitive decline. Electroencephalography is a diagnostic tool that is perfectly suited for the detections and assessment of these alterations. The aim of this doctoral thesis was to explore and characterize EEG-based biomarkers of vigilance dysfunction in patients with mild cognitive impairment due to AD (ADMCI), the early stage of the disease. Specifically, I studied the possible effects on the sources of rsEEG of cortical hyperexcitability due to epileptiform activity and the degeneration of ascending subcortical arousal systems using advanced EEG analyses. This thesis comprises two complementary studies. In the first study we analyzed resting-state eyes-closed EEG (rsEEG) recordings from a well-defined cohort of ADMCI patients (N=62) and healthy controls (N=38), using source localization with exact low-resolution electromagnetic tomography (eLORETA). The study identified a subgroup of ADMCI patients (N=8) with subclinical epileptiform EEG activity (EEA) and demonstrated significantly increased delta band activity localized to temporal and occipital cortices. These findings suggest that subclinical cortical hyperexcitability is associated with abnormal slowing in cortical rhythms, reflecting early network disruption in regions critical for memory and sensory integration. In the second study we employed a novel EEG protocol assessing transitions from wakefulness to light non-REM sleep (using the staging by Hori et al. [1]) to evaluate vigilance regulation. This study found that ADMCI patients exhibited attenuated posterior alpha desynchronization and enhanced frontal delta activity during the wake-sleep transition, in contrast to age-matched cognitively normal individuals. These EEG alterations correspond to neuropathological degeneration in subcortical structures, namely the basal forebrain cholinergic nuclei, locus coeruleus, and thalamic relay centers, that are pivotal for arousal and maintenance of vigilance, supporting a model where impaired neuromodulatory inputs lead to thalamocortical dysrhythmia and disruption of vigilance states. The findings from these studies highlight a complex interplay between subcortical degeneration and the cortical generators of EEG activity in the early stages of AD. EEG source analyses provide a powerful, non-invasive means to detect these abnormalities, offering new candidate biomarkers for vigilance-related dysfunctions. Importantly, EEG markers of delta and alpha source alterations may represent a useful tool in the detection, stratification and prognosis of the disorders of vigilance stages in ADMCI patients, further reaffirming the role of the tool in the clinical assessment of AD patients. If validated in larger prospective studies, these measures could be integrated into routine clinical evaluation, enhancing and further promoting precision medicine in AD management.