Frontal white matter volume and delta EEG sources negatively correlate in awake subjects with mild cognitive impairment and Alzheimer's disease

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Abstract

Objective

A relationship between brain atrophy and delta rhythmicity (1.5–4 Hz) has been previously explored in Alzheimer's disease (AD) subjects [Fernandez A, Arrazola J, Maestu F, Amo C, Gil-Gregorio P, Wienbruch C, Ortiz T. Correlations of hippocampal atrophy and focal low-frequency magnetic activity in Alzheimer disease: volumetric MR imaging-magnetoencephalographic study. Am J Neuroradiol. 2003 24(3):481–487]. In this study, we tested the hypothesis that such a relationship does exist not only in AD patients but also across the continuum of subjects with mild cognitive impairment (MCI) and AD.

Methods

Resting, eyes-closed EEG data were recorded in 34 MCI and 65 AD subjects. EEG rhythms of interest were delta (2–4 Hz), theta (4–8 Hz), alpha 1 (8–10.5 Hz), alpha 2 (10.5–13 Hz), beta 1 (13–20 Hz), and beta 2 (20–30 Hz). EEG cortical sources were estimated by LORETA. Cortical EEG sources were correlated with MR-based measurements of lobar brain volume (white and gray matter).

Results

A negative correlation was observed between the frontal white matter and the amplitude of frontal delta sources (2–4 Hz) across MCI and AD subjects.

Conclusions

These results confirmed for the first time the hypothesis that the sources of resting delta rhythms (2–4 Hz) are correlated with lobar brain volume across MCI and AD subjects.

Significance

The present findings support, at least at group level, the ‘transition hypothesis’ of brain structural and functional continuity between MCI and AD.

Introduction

Mild cognitive impairment (MCI) is a clinical state between elderly normal cognition and dementia featuring memory complaints and cognitive impairment on neuropsychological testing, but no dementia (Flicker et al., 1991, Petersen et al., 1995, Petersen et al., 2001). MCI is regarded a precursor of Alzheimers' disease (AD) (Arnaiz and Almkvist, 2003, Galluzzi et al., 2001, Scheltens et al., 2002), since recent studies have shown a high rate of progression to AD (Bachman et al., 1993, Gao et al., 1998, Petersen et al., 2001). In cognitively intact elders, the incidence of AD ranges from 0.17 to 3.86% (Frisoni et al., 2004, Petersen et al., 2001), while in patients with MCI it is much higher, ranging from 6 to 25% (Petersen et al., 2001). However, the ‘transition’ hypothesis is challenged by observations indicating that not all MCI patients deteriorate over time (Bennett et al., 2002, Larrieu et al., 2002), as AD cumulative incidence rates ranged from 40 to 60% (Bennett et al., 2002, Fisk et al., 2003, Larrieu et al., 2002).

MCI patients that will convert to dementia are the ideal target of preventive therapeutic strategies (Braak and Braak, 1991, Rogers et al., 1996, Small et al., 1995) and might be identified with functional and structural imaging techniques. Previous studies have successfully investigated the electrophysiological substrate of AD. In mild AD, electroencephalographic (EEG) rhythms differ from normal elderly (Nold) and vascular dementia subjects, AD patients featuring an excess of delta (0–4 Hz) and a significant decrement of posterior alpha rhythms (8–12 Hz; Babiloni et al., 2004a, Dierks et al., 1993, Dierks et al., 2000, Huang et al., 2000, Jeong, 2004, Ponomareva et al., 2003). EEG rhythm abnormalities in dementia have been associated with altered regional cerebral blood flow (rCBF)/metabolism and cognitive function (Celsis et al., 1990, Ihl et al., 1989, Jeong, 2004, Joannesson et al., 1977, Nobili et al., 2002a, Nobili et al., 2002b, Passero et al., 1995, Rodriguez et al., 1998, Rodriguez et al., 1999a, Rodriguez et al., 1999b, Sheridan et al., 1988, Sloan et al., 1995, Szelies et al., 1992). Similarly, MCI subjects have shown a decrease of alpha power when compared to normal elderly subjects (Babiloni et al., in press, Babiloni et al., in press, Koenig et al., 2005, Zappoli et al., 1995, Elmstahl and Rosen, 1997, Huang et al., 2000, Jelic et al., 2000).

Several other studies with magnetic resonance imageign (MRI) have demonstrated that structural changes of brain volume characterize AD (de Leon et al., 2004). Algorithms denoting gray matter loss or white matter changes (voxel-based morphometry, VBM) have shown medial temporal lobe atrophy as well as temporoparietal atrophy in mildly to moderately severe AD patients (Baron et al., 2001, Frisoni et al., 2002, Ohnishi et al., 2001, Rombouts et al., 2000). In MCI subjects, these algorithms have also detected atrophy in the medial temporal lobe, temporal neocortex, superior parietal lobule, anterior cingulate gyrus, and thalamus (Chetelat et al., 2002, Pennanen et al., 2005). Other techniques of structural MRI analysis have corroborated the finding of medial temporal atrophy in MCI subjects, which is also the most common MRI finding in AD patients (Testa et al., 2004, Wolf et al., 2003). Based on these data, one can speculate that the aforementioned changes of EEG rhythms in MCI and AD are related to loss of neurons in limbic and neocortical regions. Indeed, the bilateral reduction of hippocampal and entorhinal volumes of AD subjects has been recently correlated with an increment of cortical delta rhythms (Fernandez et al., 2003).

To the best of our knowledge, the relationship between brain atrophy and EEG rhythms has not been explored in MCI subjects. In this study, we test the hypothesis that such a relationship does exist not only in AD patients but across the continuum between MCI and AD, in line with the idea that MCI is often due to underlying neurodegenerative processes. Cortical sources of resting EEG rhythms in MCI and mild AD subjects were estimated by low-resolution brain electromagnetic tomography (LORETA; Pascual-Marqui and Michel, 1994, Pascual-Marqui et al., 1999, Pascual-Marqui et al., 2002), which has been successfully used in recent studies on physiological and pathological aging (Babiloni et al., 2004a, Babiloni et al., 2005a, Babiloni et al., 2005b, Dierks et al., 2000). The main statistical analysis aimed at evaluating two working hypotheses. A preliminary control hypothesis was that lobar EEG sources as revealed by the LORETA solutions had amplitude sensitivity to the cognitive status of recruited subjects. The experimental hypothesis stated a correlation between lobar brain volumes and EEG sources across MCI and mild AD subjects.

Section snippets

Methods

We have extensively described in recent papers part of the procedures (EEG recordings and LORETA analysis) pertinent to the current study as well as a description of the potential meaning of cortical rhythms in aging (Babiloni et al., 2004a, Babiloni et al., 2005a, Babiloni et al., 2005b). The previous studies aimed at analyzing (i) the distributed EEG sources specific to mild AD as compared to vascular dementia or normal aging (Babiloni et al., 2004a); (ii) the distributed EEG sources during

Topography of the EEG cortical sources as estimated by LORETA

For illustrative purposes, Fig. 1 maps the grand average of the LORETA solutions (i.e. relative z-current density at cortical voxels) modeling the distributed EEG sources for delta, theta, alpha 1, alpha 2, beta 1, and beta 2 bands in Nold, MCI−, MCI+ and mild AD groups. The Nold group presented alpha 1 sources with the maximal values of amplitude distributed in parieto-occipital regions. Delta, theta and alpha 2 sources had moderate amplitude values when compared to alpha 1 sources. Finally,

Sources of delta and alpha rhythms change across Nold, MCI and AD subjects

A preliminary control analysis allowed the modeling of resting EEG sources (LORETA solutions) sensitive to global cognitive status (MMSE score) in the recruited Nold, MCI, and mild AD subjects. When compared to Nold subjects, EEG rhythms in MCI and mild AD subjects were characterized by a marked magnitude decrease of alpha 1 sources in parieto-occipital and temporal areas. In mild AD subjects, they were also characterized by a marked magnitude increase of frontal, parieto-occipital, and

Conclusions

We have confirmed for the first time the hypothesis that sources of the resting EEG rhythms are correlated with spatially corresponding lobar brain volume across MCI and AD subjects. We found a negative correlation between the frontal delta sources with global cognitive status (MMSE) and the volume of frontal WM. The present findings further support the ‘transition hypothesis’ of brain structural and functional continuity between MCI and mild AD, at least at group level. They also prompt future

Acknowledgements

We thank Dr/Prof. Lanuzza Bartolo, Francesca Bergami, Leonardo Frigerio, Massimo Gennarelli, Nicola Girtler, and Katiuscia Sosta for their precious help in the development of the present study. We thank also Prof. Fabrizio Eusebi for his continuous support. The reaserch was grated by Association Fatebenefratelli for Research (AFaR)

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