Phd in CLINICAL EXPERIMENTAL NEUROSCIENCE AND PSYCHIATRY

Thesis title: ABNORMAL RESTING-STATE EEG ALPHA RHYTHMS AS A NEUROPHYSIOLOGICAL BIOMARKER OF VIGILANCE DYSFUNCTIONS IN PATIENTS WITH COGNITIVE DEFICITS DUE TO ALZHEIMER’S AND PARKINSON’S DISEASES

The electroencephalographic recording typically shows resting state posterior electroencephalographic (rsEEG) oscillatory activity characterized by ample alpha rhythms at 8–12 Hz frequencies distributed in posterior regions of the scalp. These ample alpha rhythms may reflect oscillatory neurophysiological mechanisms of thalamus-cortical neural synchronization related to the thalamic gating of neural signals arousing the cerebral cortex with a general effect of cortical inhibition of primary and associative cortical areas. This in turn contributes to the regulation, in physiological condition, of quiet vigilance. In pathological aging, previous rsEEG investigations have used low-resistance EEG recordings to demonstrate abnormalities in alpha and other rhythms in patients with various cognitive deficits due to Alzheimer's and Parkinson's disease. However, due to methodological advancements and insights, much has to be done in this research line, contributing in the development of new therapeutic approaches and knowledge. The aim of this thesis work was therefore to use advanced analysis techniques to understand the alpha alterations underlying the regulation of the quiet vigilance in patients with mild cognitive impairment and dementia due to Alzheimer's disease (ADMCI, ADD) and in in patients with dementia due to Parkinson's disease (PDD). Three rsEEG studies were performed for that purpose. In the first study, we hypothesized that the vigilance dysregulation seen in ADD and PDD patients might be reflected by altered reactivity of posterior rsEEG alpha rhythms during the vigilance transition from an eyes-closed to an eyes-open condition. We used clinical, demographical, and rsEEG datasets in 28 healthy elderly (Healthy), 73 PDD, and 35 ADD participants. Results showed substantial (> -10%) reduction (reactivity) in the posterior alpha source activities from the eyes-closed to the eyes-open condition in 88% of the Healthy seniors, 57% of the ADD patients, and only 35% of the PDD patients. In these alpha-reactive participants, there was lower reactivity in the parietal alpha source activities in the PDD group than in the Healthy and the ADD groups. These results suggest that ADD and more PDD are characterized by poor reactivity of mechanisms desynchronizing posterior rsEEG alpha rhythms in response to visual inputs. In the second study, we tested the exploratory hypothesis that rsEEG alpha rhythms may be sensitive to mild cognitive impairment due to AD (ADMCI) progression at a 6-month follow-up (a relevant feature for intervention clinical trials). Clinical, neuroimaging, and rsEEG datasets in 52 ADMCI and 60 Healthy seniors were used. We applied the same methodology used for the first study. Results showed a substantial (> -10%) reduction in the posterior alpha source activities during the eyes-open condition in about 90% and 70% of the Healthy and ADMCI participants, respectively and at the baseline. In all ADMCI participants with “reactive” rsEEG alpha source activities, posterior alpha source activities during the eyes-closed condition reduced in magnitude at that follow-up. These effects could not be explained by neuroimaging and neuropsychological biomarkers of AD. These results suggest that in ADMCI patients, the (“reactive”) posterior rsEEG alpha rhythms, when present, are quite sensitive to the effects of the disease progression on neurophysiological mechanisms underpinning vigilance regulation. In the third study, we tested the exploratory hypothesis that abnormalities in the rsEEG alpha rhythms may be greater in ADMCI patients than those with MCI not due to AD (noADMCI). Furthermore, they may be associated with the diagnostic cerebrospinal fluid (CSF) biomarkers (beta amyloid and tau). An international database provided clinical-demographic-rsEEG datasets for cognitively unimpaired older (Healthy; N = 45), ADMCI (N = 70), and noADMCI (N = 45) participants. Posterior rsEEG alpha source activities were reduced in the ADMCI group compared to the Healthy and noADMCI groups (p < 0.001). Negative associations between the CSF phospho-tau and total-tau levels and the posterior rsEEG alpha source activities were observed in the ADMCI group (p < 0.001). In contrast, those with CSF amyloid beta 42 were marginal. These results suggest that neurophysiological brain neural oscillatory synchronization mechanisms regulating cortical arousal and vigilance through rsEEG alpha rhythms are mainly affected by brain tauopathy in ADMCI patients and not in noADMCI patients. The results of the three studies unveiled the significant extent to which the well-known impairments in the cholinergic and dopaminergic neuromodulatory ascending systems could affect the brain neurophysiological oscillatory mechanisms underpinning posterior rsEEG alpha rhythms during quiet vigilance regulation in AD and related (i.e., PD) diseases with cognitive deficits. The results enriched the neurophysiological model underlying their known difficulties in remaining awake in quiet environmental conditions during the daytime and neurophysiological brain neural oscillatory synchronization mechanisms regulating cortical arousal and vigilance through rsEEG alpha rhythms are mainly affected by brain tauopathy in ADMCI patients. They also encouraged the use of rsEEG alpha measures in AD clinical trials aimed at developing effective therapies for vigilance dysfunctions in these patients.