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Brain Functional Network in Alzheimer's Disease: Diagnostic Markers for Diagnosis and Monitoring

Brain Functional Network in Alzheimer's Disease: Diagnostic Markers for Diagnosis and Monitoring SAGE-Hindawi Access to Research International Journal of Alzheimer’s Disease Volume 2011, Article ID 481903, 10 pages doi:10.4061/2011/481903 Review Article Brain Functional Network in Alzheimer’s Disease: Diagnostic Markers for Diagnosis and Monitoring Guido Rodriguez, Dario Arnaldi, and Agnese Picco Department of Neurosciences, Ophthalmology, and Genetics, Clinical Neurophysiology Unit, University of Genoa, De Toni street 5, 16132 Genoa, Italy Correspondence should be addressed to Dario Arnaldi, dario.arnaldi@gmail.com Received 14 December 2010; Revised 8 March 2011; Accepted 22 March 2011 Academic Editor: Giuseppe Curcio Copyright © 2011 Guido Rodriguez et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Alzheimer’s disease (AD) is the most common type of dementia that is clinically characterized by the presence of memory impairment and later by impairment in other cognitive domains. The clinical diagnosis is based on interviews with the patient and his/her relatives and on neuropsychological assessment, which are also used to monitor cognitive decline over time. Several biomarkers have been proposed for detecting AD in its earliest stages, that is, in the predementia stage. In an attempt to find noninvasive biomarkers, researchers have investigated the feasibility of neuroimaging tools, such as MR, SPECT, and FDG-PET imaging, as well as neurophysiological measurements using EEG. In this paper, we investigate the brain functional networks in AD, focusing on main neurophysiological techniques, integrating with most relevant functional brain imaging findings. 1. Introduction onset of AD symptoms. Thus, a failure of the regions of a net- work to interact at a high level of coordination may underpin Amnesic mild cognitive impairment (MCI) is characterized the cognitive disorders which are present in AD. The failure by memory impairment, either associated or not with mild of network function may be due to interaction failure among deficit in other cognitive domains whereas the function of the regions of a network, which is denoted as the disconnec- daily living is essentially preserved [1–3]. Annual conver- tion hypothesis [15]. The breakdown is thought to be due to sion rate from normality to dementia of Alzheimer’s type chronically progressive AD neuropathology with underlying (Alzheimer’s disease, AD) ranges between 0.2% and 4% [3, 4] molecular mechanisms leading downstream to neuronal whereas that from MCI to AD is between 6% and 25% and synaptic dysfunction and ultimately to neuronal loss. [3, 5]. It is an open issue with important clinical implications Such AD-characteristic structural and functional changes whether or not MCI is essentially a prodromic stage of AD are hypothesized to reflect, at least partially, the progressive [3]. impairment of fiber tract connectivity and integrity [16–18], Although clinical manifestations of cognitive dysfunction suggesting that disconnection in AD is evident at both the and impairments of activities of daily living are the current functional and structural level. standard measures for the diagnosis of AD, biomarkers are Advances in electroencephalographic (EEG) signal anal- receiving increasing attention in research centers as possible ysis permit relatively precise localization of brain neural early diagnostic surrogate measures of the ongoing pathology sources and the ability to track their hierarchical connectivity in sustaining a given function. This information can be inte- [6]. Not surprisingly, there is already a growing literature of biomarkers associated with the transition of MCI to AD [7– grated with structural and functional imaging provided by 14]. fluorodeoxyglucose (FDG) positron emission tomography Connectivity plays a critical role in mediating cognitive (PET), perfusion single-photon emission computed tomog- function. The breakdown of connectivity, both in the func- raphy (SPECT), and functional magnetic resonance imag- tional and structural system domain, plays a major role in the ing (fMRI). Such integrated measures can index patterns of 2 International Journal of Alzheimer’s Disease neural activation responsible for sensory perception, atten- object of current investigation and partly not understood. tion, memory, movement, and higher mental operations The biological complexity of the brain modular function and including language and thought, since electromagnetic sig- the physical “sum” effect of different brain electrical fields nals change in parallel over time and task, and can be on surface EEG recordings make the understanding of EEG impaired directly during such activity [19]. components a very difficult task. Actually, in the new guidelines for the AD diagnosis [20], In general, EEG changes are well related to cognitive EEG is not mentioned as a diagnostic measurement, instead dysfunction in AD. Moreover, cognitive impairment is asso- of giving greater emphasis on MRI, cerebrospinal fluid ciated with a reduction or loss of EEG reactivity in AD (CSF), PET, and genetic findings. [22]. Normal alpha was shown to be suppressed during The associations between brain pathology and indices of eye opening in AD patients with significantly higher WAIS functional and structural connectivity may help our under- performance IQ scores whereas in AD patients with irregular standing of the role of connectivity in brain function [15]. alpha it does not or only weakly change during eye opening The aim of this review is to investigate the brain func- [23]. tional network in AD focusing on main neurophysiological The most frequent findings are the power reduction of techniques and integrating the results with functional brain beta activity and alpha rhythm, the power increase of slow imaging findings. We will mainly review studies using EEG activities in the theta bands in milder dementias, and of delta data to investigate functional networks; moreover, some activities in more severe dementia. Both intrahemispheric very recent studies utilizing PET and SPECT to investi- and interhemispheric coherence of fast and alpha EEG gate functional brain imaging of AD-related pathology are activities is reduced in neurodegenerative diseases causing reported. dementia, thus suggesting a reduction of neural connections. On the contrary, coherence in delta and theta bands have been reported to be increased in AD, but this data is 2. Functional Network not agreed upon by all researchers [24]. The alpha (or background activity) also suffers from the slowing-down of 2.1. EEG in Normal Aging. Studies in normal elderly indi- its frequency, often till its peak falls below the 8–8.5 Hz. This viduals have consistently showed that healthy ageing is not phenomenon can happen together with a true increase of the associated with substantial EEG changes, which instead are theta power. caused by pathological conditions. Usually, the EEG signal According to the “transition” hypothesis that considers is elaborated (quantitative EEG-qEEG) performing a fast MCI as a “reservoir” of patients possibly developing demen- Fourier transform (FFT) in order to estimate the power tia, mainly of the AD type, EEG studies have tried to density of selected EEG frequency band, providing a power highlight early changes. Considered altogether, it is difficult spectrum and high-density spatial EEG mapping of each to identify MCI patients from normal controls, but emerging frequency band. data is consistent with the hypothesis that those who will A tendency toward a slower alpha rhythm has been convert to dementia already show similar EEG changes as reported in the elderly subjects, but it is poorly significant early AD patients [7, 8, 13, 25]. Moreover qEEG features in comparison to normal adults. In fact, the normal alpha could predict longitudinal cognitive decline in normal frequency is higher than 8 Hz also in the elderly. A qEEG elderly with subjective complaints, with an overall predictive study of age-related changes during cognitive tasks revealed accuracy of 90% [26]. no conclusive differences between the young and the elderly It should be taken in mind that EEG measures electrical [21]. Therefore, it should be taken in mind that an abnormal field variations, and a number of clinical conditions can EEG in aged people should prompt further investigation to disturb the normal electrical field of the brain. For instance, disclose brain pathology, since normal aging per se is not electrolyte changes may alter the appearance and time associated with significant EEG alterations. variation of the brain-generated electrical fields, and medi- To make this point clear, it is noteworthy that slow waves cations can slow the posterior dominant rhythm. Moreover, over the temporal areas (mainly of the left hemisphere) are in assessing the frequency of the alpha rhythm, alerting occasionally seen in the EEG of normal elderly subjects. manoeuvres are essential in order to ensure that the patient The main features of these “nonpathological” slow waves are is not drowsy. Hence, a large number of conditions cause that they do not disrupt background activity, they are not the EEG to appear abnormal. In EEG practice, the clinician associated with a substantial asymmetry of the alpha rhythm, has to rely to a large extent on the clinical history and their morphology is usually rounded, and their voltage is the neurological examination findings to make a clinically usually greater than 60–70 μV. Moreover, they are attenuated meaningful conclusion. by mental activity and eye opening, and their prevalence is In summary, a shift-to-the-left of background activity increased by drowsiness and hyperventilation. Finally, they and the increase of theta power are the earliest and more occur sporadically as single waves or in pairs, not in longer robust features of AD. When the disease progresses to its rhythmic trains. moderate stage, theta activities increase further and delta activities appear. In the most severe stages, delta and theta 2.2. The Role of EEG in AD. Although EEG is the only clinical activities increase again while the background activity cannot be longer recognized. These increasing EEG changes accord- diagnostic instrument directly reflecting cortical neuronal functioning, the genesis of surface EEG rhythms is still the ing to severity of AD have been highlighted by a study based International Journal of Alzheimer’s Disease 3 Normal 4 8 12 16 24 30 (Hz) 6 GDS 3 4 8 12 16 24 30 (Hz) GDS 4 0 10 4 8 12 16 24 30 (Hz) GDS 5 4 8 12 16 24 30 (Hz) GDS 6 4 8 12 16 20 30 (Hz) Figure 1: Sample of visual EEG and EEG spectrum on 4 clinical classes of severity (Global Deterioration Scale: GDS, from 3 to 6; for more details see text). EEG frequency bands (X-axis) and percent value of each band (Y -axis) are shown. on 4 clinical classes of severity (GDS, from 3 to 6, Figures 1 Theta rhythms are usually not appreciated in normal and 2)[27]. awakening EEG. However, a theta power increase is observed over the frontal and temporal areas during learning and memory tasks. The theta rhythms that are recorded during 2.3. Pathophysiology of EEG Changes in AD. With this basis, these tasks are thought to be produced by the activation of the understanding of pathophysiology of EEG changes in septal-hippocampal system. Hippocampus has a cholinergic AD is even more complex and just some general concepts innervation originating from basal forebrain, the medial can be commented. Scalp alpha rhythms (8–13 Hz) mainly septum, and the vertical limb of the diagonal band of Broca. result from sequences of inhibitory (IPSP) and excitatory Populations of GABAergic and glutamatergic neurons have (EPSP) postsynaptic potentials at the dendrites of cortical also been described in several basal forebrain structures. The pyramidal neurons. These potentials depend mainly on the synchronized depolarization of hippocampal neurons pro- influence of near and distant cortical modules [28], as well as on the interactions of excitatory corticothalamocortical duces field potentials that have a main frequency of 3–12 Hz and are usually known as hippocampal theta rhythm [31]. A relay fibres and inhibitory thalamic reticular fibres [29, cholinergic-glutamatergic hypothesis of AD, in which most 30]. Cholinergic and glutamatergic synapses are especially symptoms may be explained by cholinergic-glutamatergic involved in the genesis of these potentials. In Alzheimer’s disease (AD), characterized by an early cholinergic (and deficits, has been advanced. Neuronal injury/loss may in- possibly glutamatergic) deficit, this may produce a slowing- clude an excitotoxic component that possibly contributes down of alpha rhythm and a reduction up to disappearance to the early cholinergic deficit. This excitotoxic component of alpha rhythm in the severe stages. may occur, at least in part, at the septal level where somas 4 International Journal of Alzheimer’s Disease or cerebrovascular injuries, and at least for degenerative disease. This did not happen for functional neuroimaging, either metabolic or perfusional. This has actually slowed down these biomarkers introduction into dementia diagnos- tic criteria. Recently, Dubois et al. proposed to revise the NINCDS- ADRDA criteria for the diagnosis of AD [20]. A specific pattern on functional neuroimaging with FDG-PET has been proposed as one of the supportive features in the diagnosis of probable AD, specifically in terms of reduced glucose GDS 6 metabolism in bilateral temporal parietal regions. In fact, a reduction of glucose metabolism as seen on PET in bilateral 10 GDS 5 temporal parietal regions and in the posterior cingulate is the GDS 4 most commonly described diagnostic criterion for AD [36]. GDS 3 The newly proposed diagnostic criteria for AD entails a two-step diagnostic process, first identifying dementia syn- Controls drome (lack of episodic memory and other cognitive impair- ment) and then applying criteria based on the AD phenotype (presence of plaque and neurofibrillary tangles) [20]. As a Frequency bands matter of fact, this does not allow diagnosis in life. Further- more, the pathogenetic role of amyloid deposition in AD Figure 2: Histogram showing the relationship between 7 EEG fre- patients is still unclear, highlighting the necessity of another quency bands (2–3.5; 4–5.5; 6–7.5; 8–9.5; 10–11.5; 12–13.5;14– 22.5 Hz) and disease’s severity (normal controls and 4 clinical class- diagnostic path [37–40]. In summary, the authors propose es of severity; GDS 3 to 6). that the term “Alzheimer’s disease” should refer only to the in vivo clinicobiological expression of the disease. Obviously, prospective studies with postmortem verification are needed to validate this new proposal. Actually, metabolic changes (as of cholinergic neurons are found. This insult may modify identified by FDG-PET) associated with neocortical dysfunc- septal networks and contribute to the abnormal information tion are detectable before atrophy appears [41]. Moreover, processing observed in AD brain, including its hyperex- metabolism reductions exceeded volume losses in MCI [42], citability states. According to this theory, the increased theta and in presymptomatic early-onset familial AD [43]. Actu- production in AD would derive from hyperexcitability of the ally, a pattern of parietotemporal metabolic reductions in septal-hippocampal system [32]. MCI and AD, and frontal metabolic reductions later in the By meansofobservationsin head injurypatients, it has disease, has been established through the last decades of been suggested that delays in corticocortical fiber propa- research [44–46] and has recently been confirmed in ADNI gation may play a global role in determining human EEG PET data [47]. The usefulness of FDG-PET could be high- frequencies, increasing the amount of delta activity [33]. lighted also in detecting prodromal AD showing metabolic Increased T2 relaxation times in cortical gray matter and reductions in the anterior cingulate, posterior cingulate, and white matter were correlated with a shift in relative EEG temporal, parietal, and medial temporal cortices [48–50]. power to lower frequencies in the delta range (delta activity: Finally, several compounds have been developed for the 1–4 Hz) and reduced cognitive performance. Generally, these imaging of amyloid for PET and SPECT. The rapid develop- data are consistent with the idea that head injury somehow ment of different compounds suitable for the visualising of damages the ability of brains to form local cell assemblies amyloid during the past 10 years has led to the first promising within the global synaptic action field environment. in vivo studies of the amyloid ligands PIB (N-methyl- The increment of delta oscillations in mild cognitive im- 2-(4L -methyl aminophenyl)-6-hydroxybenzothiazole) [51] pairment (MCI) and AD subjects might be related to loss and FDDNP (2-(1-[6-[(2-[18F]fluoroethyl](methyl)ami- of hippocampal and posterior cortical neurons, which are no]-2-naphthyl]ethylidene)malononitrile) [52]; the latter impinged by cholinergic inputs. Indeed, it has been demon- compound also seems to label neurofibrillary tangles in pa- strated that early degeneration in mesial temporal cortex tients with AD. Furthermore, both compounds have shown of AD subjects can affect functional connectivity between a pattern of increased radioligand retention in patients with hippocampal formation and temporoparietal cortex [34]. AD compared with control individuals that is consistent with Furthermore, a bilateral reduction of gray matter volume AD pathology [52–54]. Accumulation of amyloid, however, in the hippocampal formation and entorhinal cortex of AD has also been reported in cognitively intact older people [37– subjects was correlated with an increment of delta rhythms 40]. In a recent paper, Oh et al. using PET imaging with in posterior cortex [9, 35]. the PIB compound, structural MRI, and cognitive measures identify two brain networks in which the degree of gray 3. Functional Brain Imaging matter volume fluctuates in a similar manner: a frontal network and a posterior network [39]. The authors suggested Historically, morphological imaging became easily a reliable diagnostic procedure for several brain disease, like neoplastic that β-amyloid deposition in older people without dementia 2–3.5 4–5.5 6–7.5 8–9.5 10–11.5 12–13.5 14–22.5 International Journal of Alzheimer’s Disease 5 may influence a wide structural network, although it is not MRI, apolipoprotein E risk gene (ApoE4), cerebrospinal fluid clear whether people with higher β-amyloid deposition will (CSF), and neuropsychological tests) does carry complemen- progress to AD. tary information, and the simple combination of classifiers Because SPECT is more widely available and cheaper trained on these different modalities can improve the than PET, it has received much attention as an alternative to diagnostic performance. Indeed, ApoE2 has been suggested PET. However, at present, the technique is not included in as having a protective effect and delaying the age of onset of the criteria proposed by Dubois et al. [20]as the diagnostic AD [73, 74]. accuracy estimates for this modality generally fall below qEEG has been analysed together with other measures the requisite 80% levels specified by the Reagan Biomarker of brain function. For instance, qEEG was analysed together Working Group [55]. with regional cerebral blood flow (rCBF) quantitative mea- surements in order to investigate the correlation between EEG activities and hypoperfusion and to assess the diagnostic accuracy of the two methods used alone or in combination. 4. Neurophysiological Evaluation of AD In a study on 42 AD patients and 18 healthy controls [75], In a clinical context, some firm points can bemadeconcern- rCBF and qEEG were correlated with one another, suggest- ing EEG in the evaluation of AD. In a more strict sense, the ing that these measurements used together are reasonably accurate in differentiating AD from healthy aging. Another main applications of EEG should be as a different diagnostic tool between dementia and other conditions characterized qEEG-SPECT (semiquantitative Tc-99 HMPAO technique) by peculiar EEG pattern such as Creutzfeldt-Jakob disease correlative study on 42 AD patients underlined that bilateral (CJD), toxic-metabolic encephalopathy, or in case of pseu- hippocampal rCBF was the perfusional index best correlated dodepressive dementia [56]. In a broader sense, EEG can be with the MMSE as well as being significantly correlated to useful to stage the severity of dementia on a pathophysiolog- qEEG [76](Figures 3, 4,and 5). ical basis, and, in AD, gives useful information for prognostic A very interesting application of qEEG measures tried to purposes [57]. Actually, all patients with moderate to severe evaluate their prognostic meaning in AD. In a preliminary study on 31 AD patients, right delta relative power predicted AD could exhibit abnormal EEGs. When a substantial part of the dominant rhythm falls within the range of theta band both the loss of activities of daily living (ADL) and death physicians should be encouraged to perform qEEG. This, in whereas right theta relative power predicted the onset of incontinence [77]. A confirmation came from an extended order to identify the so-called transition frequency between dominant and theta activity, as suggested by Klimesh [58]. group of 72 patients. Because patients were in different stages Moreover, qEEG is a highly sensitive method to evaluate the of the disease, the statistical analysis was performed in the biological effect of drugs [59, 60]. entire group as well as in the subgroup of 41 patients with Cortical sources of scalp EEG rhythms have been success- mild AD (scoring 3 or 4 on the GDS). In the whole group, the fully evaluated in AD patients by single dipole sources deeply loss of ADL was predicted by delta relative power in either located into a spherical brain model [61]. Single dipole side, incontinence was predicted by alpha relative power in sources of alpha or beta rhythms are located more anteriorly the right side, a borderline statistical significance was reached for death (P< .05). In the subgroup of mildly demented as a function of AD severity. Such “anteriorization” of the dipole source is observed in AD patients not only with patients, the loss of ADL was predicted by left delta relative respect to normal subjects but also with respect to subjects power, incontinence by both delta and alpha relative powers in the right side, and death was not significantly predicted with MCI [8, 61]. Notably, the location of the dipole sources correlates with the reduction of rCBF in anteroposterior (P = .08) [78]. and laterolateral brain axes [62]. By applying the LORETA Using both conventional visual analysis and qEEG, other technique, which elaborates solutions to compute the cortical authors found that AD patients with an abnormal EEG at sources of EEG activities, several multicenter studies have an early stage had a different pattern of cognitive decline than those (matched for severity of dementia) with a normal been performed in recent years in AD as well as in MCI, gaining substantial information [7–9, 63]. EEG. The patients with a deteriorating EEG during the first Even if not usually used in clinical practice, other neuro- year of followup subsequently showed a greater decline of praxic functions, a tendency to Parkinsonism and a higher physiological measurements could be performed in the eval- uation of AD. Event-related potentials (ERP) may reflect risk of institutionalisation than patients with a stable EEG cognitive decline in the longitudinal followup of MCI [64] during the 1st year [79]. In another study, more marked EEG abnormalities were found in patients with delusions and AD patients [65], and ERP and MRI data fusion could improve diagnostic accuracy of early AD [66]. Moreover, and hallucinations who also showed a more rapid cognitive transcranial magnetic stimulation (TMS), especially com- decline [80]. Thesameauthors also foundthat an abnormal bined with EEG, may provide useful information about the EEG and psychosis were independent predictors of disease degree and progression of AD [67–69]. progression [81]. As discussed in a recent paper [8], most of the EEG However, it is obviously important to combine multiple biomarkers in order to obtain complementary information studies in AD patients have reported a prominent decrease of to be used in clinical AD diagnosis practice. This kind of coherence at the alpha band. The reduction of alpha coher- ence in AD patients has been also found to be associated with investigation has been recently performed [41, 70–72]con- firming that each biomarker (including EEG, PET, SPECT, ApoE genetics risk of dementia; this alpha power reduction 6 International Journal of Alzheimer’s Disease 24.9 (Hz) 3.5 Mild AD 9.7 (Hz) 7.5 24.5 Figure 3: Sample of SPECT neuroimaging (Tc-99 HMPAO) and EEG brain mapping in a mild AD patient. Topographic scalp distribution of the EEG power on the 2.0 to 3.5 Hz frequency band (top right) and 4.0 to 7.5 Hz frequency band (bottom right) is shown. For more details, see text. Moderate AD 31.7 (Hz) 3.5 6.7 81.3 (Hz) 7.5 Figure 4: Sample of SPECT neuroimaging (Tc-99 HMPAO) and EEG brain mapping in a moderate AD patient. Topographic scalp distribution of the EEG power on the 2.0 to 3.5 Hz frequency band (top right) and 4.0 to 7.5 Hz frequency band (bottom right) is shown. For more details, see text. International Journal of Alzheimer’s Disease 7 Severe AD 21.6 (Hz) 3.5 81.3 (Hz) 7.5 Figure 5: Sample of SPECT neuroimaging (Tc-99 HMPAO) and EEG brain mapping in a severe AD patient. Topographic scalp distribution of the EEG power on the 2.0 to 3.5 Hz frequency band (top right) and 4.0 to 7.5 Hz frequency band (bottom right) is shown. For more details, see text. is supposed to be mediated by cholinergic deficit [82]. changes: (i) the alpha coherence decrease could be related Instead, coherence at the delta and theta bands has been to alterations in corticocortical connections whereas (ii) less straightforward. Some studies have shown a decrement the delta coherence increase suggests lack of influence of slow EEG coherence in AD patients [83] whereas others of subcortical cholinergic structures on cortical electrical have reported its increase [84]. Wada et al. [85]examined activity. intrahemispheric coherence at rest and during photic stim- Finally, the EEG correlates of biological markers have ulation in 10 AD patients. In the resting EEG, patients with been investigated in AD. Jelic et al. [86] found a positive AD had significantly lower coherence than gender- and age- correlation between levels of tau protein in the cerebrospinal matched healthy control subjects in the alpha-1, alpha-2, fluid (CSF) and delta/alpha ratio. In a subgroup with and beta-1 frequency bands. EEG analysis during photic high CSF tau levels, a strong relationship between EEG stimulation demonstrated that the patients had significantly alpha/theta and alpha/delta power ratios was found. No lower coherence, irrespective of the stimulus frequency. such correlation was found in healthy controls and mildly The changes in coherence from the resting state to the cognitively impaired individuals with elevated CSF tau stimulus condition showed significant group differences levels. ApoE 4 allele is a risk factor for late-onset AD and in the region of the brain primarily involved in visual is proposed to have an impact on cholinergic function in functioning. These findings suggest that patients with AD AD. may have an impairment of functional connectivity in both The qEEG of 31 patients with AD was recorded at the nonstimulus and stimulus conditions. This suggests a failure early stage of the disease and after a 3-year followup. Patients of normal stimulation-related brain activation in AD. In with AD were divided into several subgroups according to another study, alpha coherence was decreased significantly in the number of ApoE4 alleles, with a similar clinical severity temporo-parieto-occipital areas in the majority of patients and duration of dementia. The AD patients carrying the while significant delta coherence increase was found in a ApoE4 alleles had more pronounced slow-wave activity than few patients between frontal and posterior regions. This was AD patients without the ApoE4 alleles, although the disease expressed to a greater extent in patients with a more severe progression rate did not change. These differences in EEG cognitive impairment [84]. The authors speculated that may suggest differences in the degree of the cholinergic their findings could reflect two different pathophysiological deficit in these subgroups [87]. 8 International Journal of Alzheimer’s Disease References [16] K. Meguro, X.Blaizot, Y.Kondoh, C. Le Mestric, J. C. Baron, and C. 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Brain Functional Network in Alzheimer's Disease: Diagnostic Markers for Diagnosis and Monitoring

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Copyright © 2011 Guido Rodriguez et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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SAGE-Hindawi Access to Research International Journal of Alzheimer’s Disease Volume 2011, Article ID 481903, 10 pages doi:10.4061/2011/481903 Review Article Brain Functional Network in Alzheimer’s Disease: Diagnostic Markers for Diagnosis and Monitoring Guido Rodriguez, Dario Arnaldi, and Agnese Picco Department of Neurosciences, Ophthalmology, and Genetics, Clinical Neurophysiology Unit, University of Genoa, De Toni street 5, 16132 Genoa, Italy Correspondence should be addressed to Dario Arnaldi, dario.arnaldi@gmail.com Received 14 December 2010; Revised 8 March 2011; Accepted 22 March 2011 Academic Editor: Giuseppe Curcio Copyright © 2011 Guido Rodriguez et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Alzheimer’s disease (AD) is the most common type of dementia that is clinically characterized by the presence of memory impairment and later by impairment in other cognitive domains. The clinical diagnosis is based on interviews with the patient and his/her relatives and on neuropsychological assessment, which are also used to monitor cognitive decline over time. Several biomarkers have been proposed for detecting AD in its earliest stages, that is, in the predementia stage. In an attempt to find noninvasive biomarkers, researchers have investigated the feasibility of neuroimaging tools, such as MR, SPECT, and FDG-PET imaging, as well as neurophysiological measurements using EEG. In this paper, we investigate the brain functional networks in AD, focusing on main neurophysiological techniques, integrating with most relevant functional brain imaging findings. 1. Introduction onset of AD symptoms. Thus, a failure of the regions of a net- work to interact at a high level of coordination may underpin Amnesic mild cognitive impairment (MCI) is characterized the cognitive disorders which are present in AD. The failure by memory impairment, either associated or not with mild of network function may be due to interaction failure among deficit in other cognitive domains whereas the function of the regions of a network, which is denoted as the disconnec- daily living is essentially preserved [1–3]. Annual conver- tion hypothesis [15]. The breakdown is thought to be due to sion rate from normality to dementia of Alzheimer’s type chronically progressive AD neuropathology with underlying (Alzheimer’s disease, AD) ranges between 0.2% and 4% [3, 4] molecular mechanisms leading downstream to neuronal whereas that from MCI to AD is between 6% and 25% and synaptic dysfunction and ultimately to neuronal loss. [3, 5]. It is an open issue with important clinical implications Such AD-characteristic structural and functional changes whether or not MCI is essentially a prodromic stage of AD are hypothesized to reflect, at least partially, the progressive [3]. impairment of fiber tract connectivity and integrity [16–18], Although clinical manifestations of cognitive dysfunction suggesting that disconnection in AD is evident at both the and impairments of activities of daily living are the current functional and structural level. standard measures for the diagnosis of AD, biomarkers are Advances in electroencephalographic (EEG) signal anal- receiving increasing attention in research centers as possible ysis permit relatively precise localization of brain neural early diagnostic surrogate measures of the ongoing pathology sources and the ability to track their hierarchical connectivity in sustaining a given function. This information can be inte- [6]. Not surprisingly, there is already a growing literature of biomarkers associated with the transition of MCI to AD [7– grated with structural and functional imaging provided by 14]. fluorodeoxyglucose (FDG) positron emission tomography Connectivity plays a critical role in mediating cognitive (PET), perfusion single-photon emission computed tomog- function. The breakdown of connectivity, both in the func- raphy (SPECT), and functional magnetic resonance imag- tional and structural system domain, plays a major role in the ing (fMRI). Such integrated measures can index patterns of 2 International Journal of Alzheimer’s Disease neural activation responsible for sensory perception, atten- object of current investigation and partly not understood. tion, memory, movement, and higher mental operations The biological complexity of the brain modular function and including language and thought, since electromagnetic sig- the physical “sum” effect of different brain electrical fields nals change in parallel over time and task, and can be on surface EEG recordings make the understanding of EEG impaired directly during such activity [19]. components a very difficult task. Actually, in the new guidelines for the AD diagnosis [20], In general, EEG changes are well related to cognitive EEG is not mentioned as a diagnostic measurement, instead dysfunction in AD. Moreover, cognitive impairment is asso- of giving greater emphasis on MRI, cerebrospinal fluid ciated with a reduction or loss of EEG reactivity in AD (CSF), PET, and genetic findings. [22]. Normal alpha was shown to be suppressed during The associations between brain pathology and indices of eye opening in AD patients with significantly higher WAIS functional and structural connectivity may help our under- performance IQ scores whereas in AD patients with irregular standing of the role of connectivity in brain function [15]. alpha it does not or only weakly change during eye opening The aim of this review is to investigate the brain func- [23]. tional network in AD focusing on main neurophysiological The most frequent findings are the power reduction of techniques and integrating the results with functional brain beta activity and alpha rhythm, the power increase of slow imaging findings. We will mainly review studies using EEG activities in the theta bands in milder dementias, and of delta data to investigate functional networks; moreover, some activities in more severe dementia. Both intrahemispheric very recent studies utilizing PET and SPECT to investi- and interhemispheric coherence of fast and alpha EEG gate functional brain imaging of AD-related pathology are activities is reduced in neurodegenerative diseases causing reported. dementia, thus suggesting a reduction of neural connections. On the contrary, coherence in delta and theta bands have been reported to be increased in AD, but this data is 2. Functional Network not agreed upon by all researchers [24]. The alpha (or background activity) also suffers from the slowing-down of 2.1. EEG in Normal Aging. Studies in normal elderly indi- its frequency, often till its peak falls below the 8–8.5 Hz. This viduals have consistently showed that healthy ageing is not phenomenon can happen together with a true increase of the associated with substantial EEG changes, which instead are theta power. caused by pathological conditions. Usually, the EEG signal According to the “transition” hypothesis that considers is elaborated (quantitative EEG-qEEG) performing a fast MCI as a “reservoir” of patients possibly developing demen- Fourier transform (FFT) in order to estimate the power tia, mainly of the AD type, EEG studies have tried to density of selected EEG frequency band, providing a power highlight early changes. Considered altogether, it is difficult spectrum and high-density spatial EEG mapping of each to identify MCI patients from normal controls, but emerging frequency band. data is consistent with the hypothesis that those who will A tendency toward a slower alpha rhythm has been convert to dementia already show similar EEG changes as reported in the elderly subjects, but it is poorly significant early AD patients [7, 8, 13, 25]. Moreover qEEG features in comparison to normal adults. In fact, the normal alpha could predict longitudinal cognitive decline in normal frequency is higher than 8 Hz also in the elderly. A qEEG elderly with subjective complaints, with an overall predictive study of age-related changes during cognitive tasks revealed accuracy of 90% [26]. no conclusive differences between the young and the elderly It should be taken in mind that EEG measures electrical [21]. Therefore, it should be taken in mind that an abnormal field variations, and a number of clinical conditions can EEG in aged people should prompt further investigation to disturb the normal electrical field of the brain. For instance, disclose brain pathology, since normal aging per se is not electrolyte changes may alter the appearance and time associated with significant EEG alterations. variation of the brain-generated electrical fields, and medi- To make this point clear, it is noteworthy that slow waves cations can slow the posterior dominant rhythm. Moreover, over the temporal areas (mainly of the left hemisphere) are in assessing the frequency of the alpha rhythm, alerting occasionally seen in the EEG of normal elderly subjects. manoeuvres are essential in order to ensure that the patient The main features of these “nonpathological” slow waves are is not drowsy. Hence, a large number of conditions cause that they do not disrupt background activity, they are not the EEG to appear abnormal. In EEG practice, the clinician associated with a substantial asymmetry of the alpha rhythm, has to rely to a large extent on the clinical history and their morphology is usually rounded, and their voltage is the neurological examination findings to make a clinically usually greater than 60–70 μV. Moreover, they are attenuated meaningful conclusion. by mental activity and eye opening, and their prevalence is In summary, a shift-to-the-left of background activity increased by drowsiness and hyperventilation. Finally, they and the increase of theta power are the earliest and more occur sporadically as single waves or in pairs, not in longer robust features of AD. When the disease progresses to its rhythmic trains. moderate stage, theta activities increase further and delta activities appear. In the most severe stages, delta and theta 2.2. The Role of EEG in AD. Although EEG is the only clinical activities increase again while the background activity cannot be longer recognized. These increasing EEG changes accord- diagnostic instrument directly reflecting cortical neuronal functioning, the genesis of surface EEG rhythms is still the ing to severity of AD have been highlighted by a study based International Journal of Alzheimer’s Disease 3 Normal 4 8 12 16 24 30 (Hz) 6 GDS 3 4 8 12 16 24 30 (Hz) GDS 4 0 10 4 8 12 16 24 30 (Hz) GDS 5 4 8 12 16 24 30 (Hz) GDS 6 4 8 12 16 20 30 (Hz) Figure 1: Sample of visual EEG and EEG spectrum on 4 clinical classes of severity (Global Deterioration Scale: GDS, from 3 to 6; for more details see text). EEG frequency bands (X-axis) and percent value of each band (Y -axis) are shown. on 4 clinical classes of severity (GDS, from 3 to 6, Figures 1 Theta rhythms are usually not appreciated in normal and 2)[27]. awakening EEG. However, a theta power increase is observed over the frontal and temporal areas during learning and memory tasks. The theta rhythms that are recorded during 2.3. Pathophysiology of EEG Changes in AD. With this basis, these tasks are thought to be produced by the activation of the understanding of pathophysiology of EEG changes in septal-hippocampal system. Hippocampus has a cholinergic AD is even more complex and just some general concepts innervation originating from basal forebrain, the medial can be commented. Scalp alpha rhythms (8–13 Hz) mainly septum, and the vertical limb of the diagonal band of Broca. result from sequences of inhibitory (IPSP) and excitatory Populations of GABAergic and glutamatergic neurons have (EPSP) postsynaptic potentials at the dendrites of cortical also been described in several basal forebrain structures. The pyramidal neurons. These potentials depend mainly on the synchronized depolarization of hippocampal neurons pro- influence of near and distant cortical modules [28], as well as on the interactions of excitatory corticothalamocortical duces field potentials that have a main frequency of 3–12 Hz and are usually known as hippocampal theta rhythm [31]. A relay fibres and inhibitory thalamic reticular fibres [29, cholinergic-glutamatergic hypothesis of AD, in which most 30]. Cholinergic and glutamatergic synapses are especially symptoms may be explained by cholinergic-glutamatergic involved in the genesis of these potentials. In Alzheimer’s disease (AD), characterized by an early cholinergic (and deficits, has been advanced. Neuronal injury/loss may in- possibly glutamatergic) deficit, this may produce a slowing- clude an excitotoxic component that possibly contributes down of alpha rhythm and a reduction up to disappearance to the early cholinergic deficit. This excitotoxic component of alpha rhythm in the severe stages. may occur, at least in part, at the septal level where somas 4 International Journal of Alzheimer’s Disease or cerebrovascular injuries, and at least for degenerative disease. This did not happen for functional neuroimaging, either metabolic or perfusional. This has actually slowed down these biomarkers introduction into dementia diagnos- tic criteria. Recently, Dubois et al. proposed to revise the NINCDS- ADRDA criteria for the diagnosis of AD [20]. A specific pattern on functional neuroimaging with FDG-PET has been proposed as one of the supportive features in the diagnosis of probable AD, specifically in terms of reduced glucose GDS 6 metabolism in bilateral temporal parietal regions. In fact, a reduction of glucose metabolism as seen on PET in bilateral 10 GDS 5 temporal parietal regions and in the posterior cingulate is the GDS 4 most commonly described diagnostic criterion for AD [36]. GDS 3 The newly proposed diagnostic criteria for AD entails a two-step diagnostic process, first identifying dementia syn- Controls drome (lack of episodic memory and other cognitive impair- ment) and then applying criteria based on the AD phenotype (presence of plaque and neurofibrillary tangles) [20]. As a Frequency bands matter of fact, this does not allow diagnosis in life. Further- more, the pathogenetic role of amyloid deposition in AD Figure 2: Histogram showing the relationship between 7 EEG fre- patients is still unclear, highlighting the necessity of another quency bands (2–3.5; 4–5.5; 6–7.5; 8–9.5; 10–11.5; 12–13.5;14– 22.5 Hz) and disease’s severity (normal controls and 4 clinical class- diagnostic path [37–40]. In summary, the authors propose es of severity; GDS 3 to 6). that the term “Alzheimer’s disease” should refer only to the in vivo clinicobiological expression of the disease. Obviously, prospective studies with postmortem verification are needed to validate this new proposal. Actually, metabolic changes (as of cholinergic neurons are found. This insult may modify identified by FDG-PET) associated with neocortical dysfunc- septal networks and contribute to the abnormal information tion are detectable before atrophy appears [41]. Moreover, processing observed in AD brain, including its hyperex- metabolism reductions exceeded volume losses in MCI [42], citability states. According to this theory, the increased theta and in presymptomatic early-onset familial AD [43]. Actu- production in AD would derive from hyperexcitability of the ally, a pattern of parietotemporal metabolic reductions in septal-hippocampal system [32]. MCI and AD, and frontal metabolic reductions later in the By meansofobservationsin head injurypatients, it has disease, has been established through the last decades of been suggested that delays in corticocortical fiber propa- research [44–46] and has recently been confirmed in ADNI gation may play a global role in determining human EEG PET data [47]. The usefulness of FDG-PET could be high- frequencies, increasing the amount of delta activity [33]. lighted also in detecting prodromal AD showing metabolic Increased T2 relaxation times in cortical gray matter and reductions in the anterior cingulate, posterior cingulate, and white matter were correlated with a shift in relative EEG temporal, parietal, and medial temporal cortices [48–50]. power to lower frequencies in the delta range (delta activity: Finally, several compounds have been developed for the 1–4 Hz) and reduced cognitive performance. Generally, these imaging of amyloid for PET and SPECT. The rapid develop- data are consistent with the idea that head injury somehow ment of different compounds suitable for the visualising of damages the ability of brains to form local cell assemblies amyloid during the past 10 years has led to the first promising within the global synaptic action field environment. in vivo studies of the amyloid ligands PIB (N-methyl- The increment of delta oscillations in mild cognitive im- 2-(4L -methyl aminophenyl)-6-hydroxybenzothiazole) [51] pairment (MCI) and AD subjects might be related to loss and FDDNP (2-(1-[6-[(2-[18F]fluoroethyl](methyl)ami- of hippocampal and posterior cortical neurons, which are no]-2-naphthyl]ethylidene)malononitrile) [52]; the latter impinged by cholinergic inputs. Indeed, it has been demon- compound also seems to label neurofibrillary tangles in pa- strated that early degeneration in mesial temporal cortex tients with AD. Furthermore, both compounds have shown of AD subjects can affect functional connectivity between a pattern of increased radioligand retention in patients with hippocampal formation and temporoparietal cortex [34]. AD compared with control individuals that is consistent with Furthermore, a bilateral reduction of gray matter volume AD pathology [52–54]. Accumulation of amyloid, however, in the hippocampal formation and entorhinal cortex of AD has also been reported in cognitively intact older people [37– subjects was correlated with an increment of delta rhythms 40]. In a recent paper, Oh et al. using PET imaging with in posterior cortex [9, 35]. the PIB compound, structural MRI, and cognitive measures identify two brain networks in which the degree of gray 3. Functional Brain Imaging matter volume fluctuates in a similar manner: a frontal network and a posterior network [39]. The authors suggested Historically, morphological imaging became easily a reliable diagnostic procedure for several brain disease, like neoplastic that β-amyloid deposition in older people without dementia 2–3.5 4–5.5 6–7.5 8–9.5 10–11.5 12–13.5 14–22.5 International Journal of Alzheimer’s Disease 5 may influence a wide structural network, although it is not MRI, apolipoprotein E risk gene (ApoE4), cerebrospinal fluid clear whether people with higher β-amyloid deposition will (CSF), and neuropsychological tests) does carry complemen- progress to AD. tary information, and the simple combination of classifiers Because SPECT is more widely available and cheaper trained on these different modalities can improve the than PET, it has received much attention as an alternative to diagnostic performance. Indeed, ApoE2 has been suggested PET. However, at present, the technique is not included in as having a protective effect and delaying the age of onset of the criteria proposed by Dubois et al. [20]as the diagnostic AD [73, 74]. accuracy estimates for this modality generally fall below qEEG has been analysed together with other measures the requisite 80% levels specified by the Reagan Biomarker of brain function. For instance, qEEG was analysed together Working Group [55]. with regional cerebral blood flow (rCBF) quantitative mea- surements in order to investigate the correlation between EEG activities and hypoperfusion and to assess the diagnostic accuracy of the two methods used alone or in combination. 4. Neurophysiological Evaluation of AD In a study on 42 AD patients and 18 healthy controls [75], In a clinical context, some firm points can bemadeconcern- rCBF and qEEG were correlated with one another, suggest- ing EEG in the evaluation of AD. In a more strict sense, the ing that these measurements used together are reasonably accurate in differentiating AD from healthy aging. Another main applications of EEG should be as a different diagnostic tool between dementia and other conditions characterized qEEG-SPECT (semiquantitative Tc-99 HMPAO technique) by peculiar EEG pattern such as Creutzfeldt-Jakob disease correlative study on 42 AD patients underlined that bilateral (CJD), toxic-metabolic encephalopathy, or in case of pseu- hippocampal rCBF was the perfusional index best correlated dodepressive dementia [56]. In a broader sense, EEG can be with the MMSE as well as being significantly correlated to useful to stage the severity of dementia on a pathophysiolog- qEEG [76](Figures 3, 4,and 5). ical basis, and, in AD, gives useful information for prognostic A very interesting application of qEEG measures tried to purposes [57]. Actually, all patients with moderate to severe evaluate their prognostic meaning in AD. In a preliminary study on 31 AD patients, right delta relative power predicted AD could exhibit abnormal EEGs. When a substantial part of the dominant rhythm falls within the range of theta band both the loss of activities of daily living (ADL) and death physicians should be encouraged to perform qEEG. This, in whereas right theta relative power predicted the onset of incontinence [77]. A confirmation came from an extended order to identify the so-called transition frequency between dominant and theta activity, as suggested by Klimesh [58]. group of 72 patients. Because patients were in different stages Moreover, qEEG is a highly sensitive method to evaluate the of the disease, the statistical analysis was performed in the biological effect of drugs [59, 60]. entire group as well as in the subgroup of 41 patients with Cortical sources of scalp EEG rhythms have been success- mild AD (scoring 3 or 4 on the GDS). In the whole group, the fully evaluated in AD patients by single dipole sources deeply loss of ADL was predicted by delta relative power in either located into a spherical brain model [61]. Single dipole side, incontinence was predicted by alpha relative power in sources of alpha or beta rhythms are located more anteriorly the right side, a borderline statistical significance was reached for death (P< .05). In the subgroup of mildly demented as a function of AD severity. Such “anteriorization” of the dipole source is observed in AD patients not only with patients, the loss of ADL was predicted by left delta relative respect to normal subjects but also with respect to subjects power, incontinence by both delta and alpha relative powers in the right side, and death was not significantly predicted with MCI [8, 61]. Notably, the location of the dipole sources correlates with the reduction of rCBF in anteroposterior (P = .08) [78]. and laterolateral brain axes [62]. By applying the LORETA Using both conventional visual analysis and qEEG, other technique, which elaborates solutions to compute the cortical authors found that AD patients with an abnormal EEG at sources of EEG activities, several multicenter studies have an early stage had a different pattern of cognitive decline than those (matched for severity of dementia) with a normal been performed in recent years in AD as well as in MCI, gaining substantial information [7–9, 63]. EEG. The patients with a deteriorating EEG during the first Even if not usually used in clinical practice, other neuro- year of followup subsequently showed a greater decline of praxic functions, a tendency to Parkinsonism and a higher physiological measurements could be performed in the eval- uation of AD. Event-related potentials (ERP) may reflect risk of institutionalisation than patients with a stable EEG cognitive decline in the longitudinal followup of MCI [64] during the 1st year [79]. In another study, more marked EEG abnormalities were found in patients with delusions and AD patients [65], and ERP and MRI data fusion could improve diagnostic accuracy of early AD [66]. Moreover, and hallucinations who also showed a more rapid cognitive transcranial magnetic stimulation (TMS), especially com- decline [80]. Thesameauthors also foundthat an abnormal bined with EEG, may provide useful information about the EEG and psychosis were independent predictors of disease degree and progression of AD [67–69]. progression [81]. As discussed in a recent paper [8], most of the EEG However, it is obviously important to combine multiple biomarkers in order to obtain complementary information studies in AD patients have reported a prominent decrease of to be used in clinical AD diagnosis practice. This kind of coherence at the alpha band. The reduction of alpha coher- ence in AD patients has been also found to be associated with investigation has been recently performed [41, 70–72]con- firming that each biomarker (including EEG, PET, SPECT, ApoE genetics risk of dementia; this alpha power reduction 6 International Journal of Alzheimer’s Disease 24.9 (Hz) 3.5 Mild AD 9.7 (Hz) 7.5 24.5 Figure 3: Sample of SPECT neuroimaging (Tc-99 HMPAO) and EEG brain mapping in a mild AD patient. Topographic scalp distribution of the EEG power on the 2.0 to 3.5 Hz frequency band (top right) and 4.0 to 7.5 Hz frequency band (bottom right) is shown. For more details, see text. Moderate AD 31.7 (Hz) 3.5 6.7 81.3 (Hz) 7.5 Figure 4: Sample of SPECT neuroimaging (Tc-99 HMPAO) and EEG brain mapping in a moderate AD patient. Topographic scalp distribution of the EEG power on the 2.0 to 3.5 Hz frequency band (top right) and 4.0 to 7.5 Hz frequency band (bottom right) is shown. For more details, see text. International Journal of Alzheimer’s Disease 7 Severe AD 21.6 (Hz) 3.5 81.3 (Hz) 7.5 Figure 5: Sample of SPECT neuroimaging (Tc-99 HMPAO) and EEG brain mapping in a severe AD patient. Topographic scalp distribution of the EEG power on the 2.0 to 3.5 Hz frequency band (top right) and 4.0 to 7.5 Hz frequency band (bottom right) is shown. For more details, see text. is supposed to be mediated by cholinergic deficit [82]. changes: (i) the alpha coherence decrease could be related Instead, coherence at the delta and theta bands has been to alterations in corticocortical connections whereas (ii) less straightforward. Some studies have shown a decrement the delta coherence increase suggests lack of influence of slow EEG coherence in AD patients [83] whereas others of subcortical cholinergic structures on cortical electrical have reported its increase [84]. Wada et al. [85]examined activity. intrahemispheric coherence at rest and during photic stim- Finally, the EEG correlates of biological markers have ulation in 10 AD patients. In the resting EEG, patients with been investigated in AD. Jelic et al. [86] found a positive AD had significantly lower coherence than gender- and age- correlation between levels of tau protein in the cerebrospinal matched healthy control subjects in the alpha-1, alpha-2, fluid (CSF) and delta/alpha ratio. In a subgroup with and beta-1 frequency bands. EEG analysis during photic high CSF tau levels, a strong relationship between EEG stimulation demonstrated that the patients had significantly alpha/theta and alpha/delta power ratios was found. No lower coherence, irrespective of the stimulus frequency. such correlation was found in healthy controls and mildly The changes in coherence from the resting state to the cognitively impaired individuals with elevated CSF tau stimulus condition showed significant group differences levels. ApoE 4 allele is a risk factor for late-onset AD and in the region of the brain primarily involved in visual is proposed to have an impact on cholinergic function in functioning. These findings suggest that patients with AD AD. may have an impairment of functional connectivity in both The qEEG of 31 patients with AD was recorded at the nonstimulus and stimulus conditions. This suggests a failure early stage of the disease and after a 3-year followup. Patients of normal stimulation-related brain activation in AD. In with AD were divided into several subgroups according to another study, alpha coherence was decreased significantly in the number of ApoE4 alleles, with a similar clinical severity temporo-parieto-occipital areas in the majority of patients and duration of dementia. The AD patients carrying the while significant delta coherence increase was found in a ApoE4 alleles had more pronounced slow-wave activity than few patients between frontal and posterior regions. This was AD patients without the ApoE4 alleles, although the disease expressed to a greater extent in patients with a more severe progression rate did not change. These differences in EEG cognitive impairment [84]. The authors speculated that may suggest differences in the degree of the cholinergic their findings could reflect two different pathophysiological deficit in these subgroups [87]. 8 International Journal of Alzheimer’s Disease References [16] K. Meguro, X.Blaizot, Y.Kondoh, C. Le Mestric, J. C. Baron, and C. 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