Dementia with Lewy Bodies (DLB) presents abnormalities in frontal executive and motor functions, due to the progressive neurodegeneration by not only nigrostriatal dopaminergic but also frontostriatal, mesocortical, mesolimbic, and fronto-parietal neural networks in relation to intracellular Lewy bodies and neurofibrillary tangles (Weisman et al., 2007 PMID: 17646627). As a result, DLB clinical manifestations extend to visual hallucinations, fluctuation of cognitive disorders, and rapid eye movement (REM) sleep disorders (Donaghy and McKeith 2014 PMID: 25484925). In particular, visual hallucinations are very frequent (> 80%) in DLB patients (McKeith et al., 2017 PMID: 28592453). Our recent study showed that the amplitude of delta (about 2-4 Hz) and alpha (about 8-12 Hz) cortical sources of resting state (eyes-closed) electroencephalographic (rsEEG) rhythms might reflect different abnormalities of the core neurophysiological mechanisms underpinning brain arousal in quiet wakefulness and low vigilance in DLB patients (with mild cognitive impairment and dementia) also compared to others neurodegenerative diseases (i.e. Alzheimer¿s and Parkinson¿s disease) (Babiloni et al., 2017 PMID: 29407464). The purpose is to test the hypothesis that the cortical sources of rsEEG rhythms at delta and alpha frequencies may differ as a function of relevant clinical features in DLB patients such as the severity and fluctuation of cognitive deficits, REM behavioral disorders, and visual hallucinations. To test this hypothesis, cortical sources of rsEEG rhythms in age-, sex-, and education-matched DLB, AD, and Nold subjects will be extracted from our international archive and compared with the focus on statistical contrasts between matched DLB sub-groups with high vs. low global cognitive status, and the presence or absence of the fluctuation of cognitive disorders, visual hallucinations, and REM sleep behavior disorders.
In the present retrospective rsEEG study, the hypothesis is that the functional topography of cortical delta and alpha source activities may differ in sub-groups of demographically-matched DLB patients as a function of characterizing disease symptoms such as cognitive deficits, REM sleep behavioral disorders, fluctuations of cognitive deficits, and visual hallucinations. Here these cortical sources are considered as an outcome of brainstem-cortical and thalamus-cortical oscillatory neural synchronization mechanisms regulating the brain arousal in quiet wakefulness, as one of the neurophysiological bases of motor, cognitive, and visual perceptive functions in humans. To support this basic neurophysiological assumption, previous studies investigating rsEEG rhythms have reported that sleep deprivation induces an increase in posterior cortical delta rhythms and a reduction in widespread alpha rhythms recorded in healthy adults resting in quiet wakefulness, while the acute administration of a pharmacological agent enhancing the vigilance (i.e., Modafinil) partially recovers these effects (Chapotot et al., 2003 PMID: 12552359; James et al., 2011 PMID: 21301819; Bodenmann et al., 2009 PMID: 19726643; Saletu et al., 2007 PMID: 17187965). It has also been observed that abnormalities in cortical alpha source activities might reflect an alteration in the interplay of cholinergic projections from basal forebrain to the following oscillating neural networks involving glutamatergic high-threshold and relay-mode thalamocortical neurons, GABA interneurons, and cortical pyramidal neurons. From a translational point of view, a recent rsEEG study has reported abnormal alpha source activities in resting-state brain neural networks in DLB patients (Aoki et al., 2019 PMID: 30654367). In that study, occipital alpha source activity was reduced in DLB patients over healthy controls in a visual neural network, this abnormality being correlated with deficits in attention, visuospatial skills, and cognition possibly reflecting cholinergic impairment (Aoki et al., 2019 PMID: 30654367). Concerning the present abnormalities in delta source activities based in ADD and DLB patients, it may be generated by an abnormal synchronization of neurons of thalamus and cerebral cortex, possibly related to an altered functional connectivity in parietal, temporal, and occipital regions (Steriade and Llinas, 1988 PMID: 2839857; Klimesch, 1999 PMID: 1020923; Pfurtscheller and Lopez da Silva, 1999 PMID: 10576479). Furthermore, compared with Nold and ADD groups, DLB patients exhibited greater delta and theta rhythms (Andersson et al., 2008 PMID: 18841014; Kai et al., 2005 PMID: 16019033). The temporal fluctuation of these rhythms characterized DLB patients (Bonanni et al., 2008 PMID: 18202105) and correlated with clinical scores of cognitive fluctuations (Stylianou et al.,2018 PMID: 29656189). In these patients, the main localization of the fluctuations of delta rhythms was occipital (Bonanni et al., 2016 PMID: 27589528). The fluctuation of delta rhythms was detectable at the individual level in most of the DLB individuals (Bonanni et al., 2008 PMID: 18202105) and was used as an input to classify them from ADD patients with an accuracy higher than 90%. (Stylianou et al., 2018 PMID: 29656189). Finally, previous findings showed that DLB patients with hallucinations have greater widespread delta rhythms and higher frontal-parietal functional connectivity at scalp alpha rhythms when compared to ADD patients with hallucinations (Dauwan et al., 2018 PMID: 29653315). The present proposal could demonstrate that DLB patients with greater cognitive deficits, cognitive fluctuations, and visual hallucinations can be distinguished by different spatial patterns of delta and alpha source activities. Therefore, future studies may test the association of this different symptoms-related delta and alpha source topography with DLB neuropathological processes such as cortical ¿-synucleinopathy and intracellular Lewy bodies (Caviness et al., 2018 PMID: 29161906) and total phosphorylated ¿-synuclein (Caviness et al., 2016 PMID: 27062301). The correlation between rsEEG sources and neuropathological marker could help to monitor the pharmacological effects on brain affected by neurological diseases.