Clinical Neurophysiology 122 (2011) 1718–1725

Contents lists available at ScienceDirect

Clinical Neurophysiology
journal homepage: www.elsevier.com/locate/clinph

Differences in quantitative EEG between frontotemporal dementia and

Alzheimer’s disease as revealed by LORETA
K. Nishida a,⇑, M. Yoshimura a, T. Isotani b, T. Yoshida c, Y. Kitaura a, A. Saito d, H. Mii a, M. Kato a, Y. Takekita a,
A. Suwa a, S. Morita a, T. Kinoshita a
a
Department of Neuropsychiatry, Kansai Medical University, 10-15 Fumizono-cho, Moriguchi, Osaka 570-8506, Japan
b
Laboratory for Brain–Mind Research, Faculty of Nursing Shikoku University, Furukawa, Ojin-cho, Tokushima-shi, Tokushima 771-1192, Japan
c
Medical Ambassade du Japon en Algerie, 1 Chemin Al Bakri, Ben Aknoun, Alger, Algerie
d
Department of Neurology, Kansai Medical University, 10-15 Fumizono-cho, Moriguchi, Osaka 570-8506, Japan

a r t i c l e i n f o h i g h l i g h t s

Article history:  A comparative study of frontotemporal dementia (FTD), Alzheimer’s disease (AD), and healthy control
Accepted 14 February 2011 subjects (NC) was carried out in terms of the cortical localization of oscillatory EEG activity.
Available online 10 March 2011  As compared to NC, FTD had significantly reduced alpha generators in fronto-temporal cortices, while
AD showed significantly stronger delta generators that included the frontal lobes.
Keywords:  ROC curves demonstrate a moderate separation of FTD, AD, and NC groups.
Quantitative EEG
EEG
Frontotemporal dementia a b s t r a c t
Alzheimer’s disease
LORETA Objective: To determine the electrophysiological characteristics of frontotemporal dementia (FTD) and
Beta rhythm the distinction with Alzheimer’s disease (AD).
Sensorimotor area Methods: We performed analyses of global field power (GFP) which is a measure of whole brain electric
field strength, and EEG neuroimaging analyses with sLORETA (standardized low resolution electromag-
netic tomography), in the mild stages of FTD (n = 19; mean age = 68.11 ± 7.77) and AD (n = 19; mean
age = 69.42 ± 9.57) patients, and normal control (NC) subjects (n = 22; mean age = 66.13 ± 6.02).
Results: In the GFP analysis, significant group effects were observed in the delta (1.5–6.0 Hz), alpha1 (8.5–
10.0 Hz), and beta1 (12.5–18.0 Hz) bands. In sLORETA analysis, differences in activity were observed in
the alpha1 band (NC > FTD) in the orbital frontal and temporal lobe, in the delta band (AD > NC) in wide-
spread areas including the frontal lobe, and in the beta1 band (FTD > AD) in the parietal lobe and senso-
rimotor area.
Conclusions: Differential patterns of brain regions and EEG frequency bands were observed between the
FTD and AD groups in terms of pathological activity.
Significance: FTD and AD patients in the early stages displayed different patterns in the cortical localiza-
tion of oscillatory activity across different frequency bands.
Ó 2011 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights
reserved.

1. Introduction stereotypic behavior. Its pathological changes are limited to the

Frontotemporal lobar degeneration (FTLD) of non-Alzheimer
type dementia (Neary et al., 1998) is a progressive behavioral dis-
order primarily related to dysfunction of the frontal and anterior
temporal lobes. It encompasses a variety of clinical syndromes,
which can be divided into three subtypes. The most common sub-
type is frontotemporal dementia (FTD). The clinical features of FTD
are apathy, impulsiveness, lack of inhibition, loss of insight, and
⇑ Corresponding author. Tel.: +81 6 6992 1001; fax: +81 6 6995 2669.
E-mail address: nishidak@takii.kmu.ac.jp (K. Nishida).
frontal and temporal lobes in its early stages. In contrast, the most
common type of dementia, Alzheimer’s disease (AD), is associated
with dysfunction of the parietal lobe, occipital lobe and atrophy of
the hippocampus, and its most common symptoms are loss of
recent memory and impairment of visuospatial abilities.
Many imaging studies have been performed with magnetic res-
onance imaging (MRI) (Du et al., 2006, 2007; Young et al., 2009),
single-photon emission tomography (SPECT) (Lojkowska et al.,
2002; Varrone et al., 2002; Waragai et al., 2008) and positron emis-
sion tomography (PET) (Ishii et al., 1998; Foster et al., 2007; Mosconi
et al., 2008). Pathological changes of FTD patients occur in the fron-
tal and temporal regions, whereas in AD patients the changes are

1388-2457/$36.00 Ó 2011 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.clinph.2011.02.011
 K. Nishida et al. / Clinical Neurophysiology 122 (2011) 1718–1725 1719

observed in the medial temporal lobes, especially in the hippocam-
pus. MRI studies have shown thinning of the cortex in those regions.
SPECT and PET studies have shown frontal and anterior temporal
hypoperfusion in FTD patients, and parieto-occipital hypoperfusion
in early stage AD patients. These imaging methods constitute reli-
able preclinical tools for distinguishing these diseases. However,
MRI, SPECT, and PET by themselves are not sufficient to provide
information on disease process and mechanism of dementia espe-
cially in the early stages. Furthermore, sometimes these imaging
tools are not clinically feasible or impose a heavy burden on the pa-
tient because of their invasiveness. In contrast, electroencephalog-
raphy (EEG) is a non-invasive technique that is very sensitive to
changes in the functional state of the human brain.
Many studies have shown that AD is associated with visual and
quantitative EEG changes (Dierks et al., 1993; Babiloni et al., 2004,
2007, 2009; Yoshimura et al., 2004; Koenig et al., 2005; Rossini
et al., 2006; Lehmann et al., 2007; Luckhaus et al., 2008; Park
et al., 2008). The EEGs in AD patients are characterized by an in-
crease in slow (delta and/or theta) activity and a decrease in fast
(alpha and/or beta) activity. Babiloni reported that occipital delta
(2–4 Hz) and alpha1 (8–10.5 Hz) sources in parietal, occipital, tem-
poral, and limbic areas had an intermediate magnitude in MCI sub-
jects compared to mild AD and normal old subjects (Babiloni et al.,
2007).
In contrast, visual inspection of the EEGs of FTD patients have
been reported as almost normal until the advanced stage of the dis-
ease (Neary et al., 1998). Julin et al. (1995) reported that when they
compared only patients with mild stage (MMSE > 22), the EEG
showed significantly less abnormal changes for the frontal lobe
dementia (FLD) patients as compared to the AD group. However,
Chan et al. (2004) reported no significant difference in the severity
of EEG abnormality between the FTLD and AD patient groups
despite the fact that visual EEG changes were found in AD patients
in early stages. The recent increasing number of quantitative EEG
(qEEG) findings for FTD patients indicates otherwise. Passant et
al. (2005) found that the EEG was normal in the late-onset group,
while it was mildly and variably abnormal in the early-onset group.
Some studies have compared AD and FTD groups (Yener et al., 1996;
Lindau et al., 2003; Pijnenburg et al., 2004; Yoland et al., 2008; de
Haan et al., 2009). Yener found that the most informative qEEG
variables for distinguishing FTD from AD were the left parietal theta
(4–8 Hz) and Delta (0–4 Hz) frequency bands, the right parietal
alpha (8–12 Hz) band, the left frontal theta (4–8 Hz) band, and
the left temporal beta2 (18–26 Hz) band. The mean relative powers
of the left temporal beta2 (18–26 Hz) and left parietal theta
(4–8 Hz) bands were higher for AD than for FTD, while those of
the right parietal beta2 (18–26 Hz) and right parietal alpha
(8–12 Hz) bands were lower in AD than in FTD. Lindau et al.
(2003) reported that FTD did not differ from controls in the delta
(1.0–3.5 Hz), and theta (4.0–7.5 Hz) band, but there was tendency
in FTD to a larger decrease in alpha (8.0–11.0 Hz), and beta1–beta3
(12.0–23.5 Hz) band compared to controls than in AD. In contrast,
the AD group was significantly decreased in the delta (1.0–3.5 Hz)
band compared to normal controls.
Using graph-theory derived methods applied to scalp-recorded
EEG, de Haan et al. (2009) reported that the mean normalized clus-
tering coefficient was smaller in AD compared to controls in the
lower alpha and beta frequency bands, and that FTLD showed a
non-significant but constant trend in the opposite direction in
the higher frequency bands. In addition, they found that the med-
ian values of AD and FTLD changed in opposite directions in all fre-
quency bands.
These studies show the effectiveness of EEG in assessing
dementias, which can be enhanced by using other methods for
analyzing EEG data. Thus, it is important to determine the EEG
characteristics of FTD patients for the differential diagnosis. Under-
standing its characteristics in early stages will greatly help in treat-
ment selection and social support (Mioshi et al., 2009). The aim of
this study was to investigate the electrophysiological characteris-
tics of FTD and the distinction with AD, especially spatial EEG
analysis.
2. Materials and methods
2.1. Subjects
All the patients that were diagnosed with AD or FTD in the
Neuropsychiatry Clinic of Kansai Medical University Takii Hospital
between June 2007 and May 2009 were examined as candidates for
this study. All patients were diagnosed on the basis of information
obtained from an extensive clinical history and physical examina-
tion, and excluded mood disorder, schizophrenia, and anxiety dis-
order. In addition, patients underwent brain MRI, I123-IMP-SPECT,
and Mini Mental State Examination (MMSE) (Folstein et al.,
1975). All FTD patients showed either frontal temporal mild atro-
phy on MRI and/or mild hypoperfusion on SPECT. All AD patients
showed either mild temporal atrophy or diffusional atrophy on
MRI and/or parieto-occipital hypoperfusion on SPECT. An experi-
enced neuroradiologist assessed these atrophies and hypoperfu-
sion by visual inspection of MRIs and with computer-assisted
statistical analysis of brain perfusion SPECT images. The severity
of dementia was assessed using the clinical dementia rating
(CDR) scale (Hughes et al., 1982). Only patients with mild dementia
(0.5 6 CDR 6 1.0) were included in this study. For the diagnosis of
FTD, the Lund and Manchester criteria (Neary et al., 1998) were
employed. Patients with semantic dementia or progressive non-
fluent aphasia were excluded from this study. For the diagnosis
of probable AD, the diagnostic criteria of the National Institute of
Neurological and Communicative Disorders and Strokes–Alzhei-
mer’s Disease and Related Disorders Association (NINCDS–ADRDA)
(McKhann et al., 1984) and the Diagnostic and Statistical Manual of
Mental Disorder-IV (DSM-IV, 1994) were employed. None of the
patients with AD had received anticholinesterase therapy.
Nineteen patients with FTD (7 males and 12 females; age range:
51–78 years; mean age ± s.d. = 68.11 ± 7.77; MMSE score ± s.d. =
23.84 ± 3.13), and 19 patients with AD (6 males and 13 females;
age range: 50–82 years; mean age ± s.d. = 69.42 ± 9.57; MMSE
score ± s.d. = 21.05 ± 3.13) were included in this study. The pa-
tients were all right-handed and were not taking psychoactive
medication. FTD patients underwent the frontal assessment bat-
tery (FAB) (Dubois et al., 2000) which is a simple tool for assessing
frontal lobe function and useful method to diagnose of FTD (Oguro
et al., 2006) (mean FAB score ± s.d. = 11.42 ± 2.91). We collected
the patient’s main and first symptoms hearing from the caregiver.
All AD patients exhibited memory loss. At disease onset, the FTD
patients were heterogeneously exhibiting the following character-
istics: 6/19 with apathy, 6/19 with agitation, 4/19 were disinhibit-
Table 1
Demographic data of the subjects in this study.
FTD (n = 19) AD (n = 19) NC (n = 22) P value
Sex (m:f) 7:12 6:13 10:12 0.66
Age 68.11 ± 7.77 69.42 ± 9.57 66.13 ± 6.02 0.41
MMSE 23.84 ± 3.13* 21.05 ± 2.44** 28.72 ± 1.83 *
p < 0.0002
**
p < 0.0001
FAB 11.42 ± 2.91
Education 10.58 ± 2.71 10.74 ± 2.88 12.14 ± 2.17 0.099
Duration of the 22.68 ± 9.86 20.05 ± 7.56 0 0.362
disease
CDR (0:0.5:1) 0:09:10 0:10:09 22:00:00
FTD: frontotemporal dementia, AD: Alzheimer’s disease; NC: normal control.
*
FTD compared with AD.
**
AD compared with NC.
1720 K. Nishida et al. / Clinical Neurophysiology 122 (2011) 1718–1725
ed, 3/19 with stereotypy, and 6/19 with physical complaints.
Twenty-two non-demented, age-matched, right-handed healthy
volunteers (12 males and 10 females; age range: 55–76 years;
mean age ± s.d. = 66.13 ± 6.02; MMSE score ± s.d. = 28.72 ± 1.83),
were recruited as normal controls (NC). The subjects had voluntar-
ily applied to participate in this study with no reward offered. Their
medical history and physical and neurological examinations
showed no signs of abnormality. Table 1 shows the demographic
data of the subjects in this study. There are no statistically signifi-
cant differences in the demographic variables (age, gender, educa-
tion, duration of the disease) among the groups (p > 0.05; one-way
ANOVA). The Institutional Ethical Review Board of Kansai Medical
University approved this study and the written informed-consent
was obtained from the patients or the caregivers.
2.2. Recording of EEG
Eyes-closed resting EEG was recorded from 19 scalp electrodes
in accordance with the international 10/20 system (Fp1, Fp2, F7,
F3, Fz, F4, F8, T3, C3, Cz, C4, T4, T5, P3, Pz, P4, T6, O1, O2) referenced
to linked ear lobes (A1 and A2). Vigilance controlled EEG recording
sessions lasted 15–20 min, with subjects receiving a warning
sound when they started to drift towards drowsiness. EEGs were
amplified, bandpass filtered to 0.3–30 Hz, sampled at 128 Hz, and
stored on a hard disk using EEG-1100 NIHON KODEN system (Ni-
hon Koden, Tokyo, Japan). After each EEG recording, 20 artifact-free
epochs of 2-s duration each were randomly selected by visual
inspection for analysis, excluding eye-movements, blinks, and
drowsiness. The selected data were recomputed against average
reference.
2.3. Global field power (GFP)
In a first step of analysis, comparisons between groups were
based on power spectra of scalp electric potentials. These data do
not rely on any assumption or source model, other than the prop-
erty of wide-sense stationary for the EEG signals. The global field
power (GFP) measure (Lehmann and Skrandies, 1980) was used,
and is defined as the standard deviation (SD) of the set of scalp
potentials, thus corresponding to the whole brain electric field
strength. GFP for the spectral amplitude was computed across
electrodes to obtain a measure of total amplitude for the seven fre-
quency bands defined by (Kubicki et al., 1979): delta (1.5–6.0 Hz),
theta (6.5–8.0 Hz), alpha1 (8.5–10.0 Hz), alpha2 (10.5–12.0 Hz),
beta1 (12.5–18.0 Hz), beta2 (18.5–21.0 Hz), and beta3 (21.5–
Fig. 1. Logarithm of grand average GFP spectra for frontotemporal dementia (FTD), Alzheimer’s disease (AD), and normal control (NC), groups.
30.0 Hz). Statistical analyses were performed using SPSS version
12.0 for Windows and the sLORETA software (Pascual-Marqui,
2002) (http://www.uzh.ch/keyinst/loreta) implementing non-
parametric randomization statistics with correction for multiple
testing (Nichols and Holmes, 2002). Relative (GFP) power for each
frequency band (percentage) was calculated as the absolute power
of each frequency band divided by absolute power of the total fre-
quency band (sum of all frequency band powers).
Repeated measures analysis of variance was used to test the
null hypothesis of ‘‘no difference between groups: FTD = AD = NC’’.
Upon rejection of this hypothesis, post-hoc tests with correction
for multiple testing were performed in order to find which groups
and which frequency bands were significantly different. Any
significant difference confirmed in this step on scalp potentials val-
idates the second analysis step, where comparisons between
groups are based on the sLORETA sources. Statistical analysis on
the cortical sources should reveal more detailed structure for the
group differences, since scalp GFP is global measure, i.e. an average
over all electrodes.
2.4. sLORETA
sLORETA computations were carried out in a realistic three-
compartment model of the head that included the scalp, skull,
and neural tissue. The actual model we used corresponds to the
digitized MNI152 template provided by the Brain Imaging Center
of the Montreal Neurological Institute (Mazziotta et al., 2001),
which is co-registered in the Talairach atlas. Electric neuronal
activity is restricted to cortical gray matter, as determined by the
Talairach Daemon (Lancaster et al., 2000). The current implemen-
tation of the software uses a total of 6239 gray-matter voxels with
a resolution of 5 mm. The lead field for this realistic head model
was computed using the boundary element method (BEM) (Fuchs
et al., 2002). The electrode coordinates were based on the average
location of the 10-5 system placement system (Jurcak et al., 2005).
We performed voxel-by-voxel tests for comparing the pairs of
groups: FTD vs NC, AD vs NC and FTD vs AD. Full correction for
multiple testing (for all voxels and all frequency bands) was imple-
mented by means of non-parametric randomization using the
maximum-statistic (Nichols and Holmes, 2002). Global subject-
wise normalization was performed (Frackowiak, 2004) prior to
group comparisons, which is equivalent to the relative global field
power of the EEG data used in the previous analysis step. SLORETA
software from the KEY Institute was used, which includes not only
 K. Nishida et al. / Clinical Neurophysiology 122 (2011) 1718–1725 1721

Table 2
Individual alpha peak frequencies: descriptive statistics and ANOVA.

FTD AD NC
Number of subjects 19 19 22
Mean alpha peak frequency (Hz) 9.35 9.11 9.50
Median 9.40 9.00 9.40
Lower quartile 8.60 9.00 9.00
Upper quartile 9.80 9.40 10.20
Standard deviation 0.76 0.58 0.80

Parametric ANOVA: p = 0.23 (not significant).

Non-parametric Kruskal–Wallis ANOVA by Ranks: p = 0.33 (not significant).
FTD: frontotemporal dementia, AD: Alzheimer’s disease; NC: normal control.

source localization, but a full statistical analysis package which Fig. 2. In delta frequency band, the relative GFP value of AD was significantly higher
than that of NC (p = 0.005). In alpha1 frequency band, the relative GFP value of NC
corrects for multiple testing.
was significantly higher than that of FTD (p = 0.014). In beta1 frequency band, the
relative GFP value of FTD was significantly higher than that of AD (p = 0.014). (FTD:
frontotemporal dementia, AD: Alzheimer disease, NC: normal control) ⁄⁄p = 0.005,
3. Results ⁄
P > 0.05.

3.1. GFP
Fig. 1 shows the logarithm of grand average GFP spectra for
FTD, AD and NC groups. These curves have the familiar form
of eyes closed EEG spectra, with the characteristic alpha peak
well within the 8–12 Hz range. The individual alpha peak fre-
quencies (for each subject) were computed. An ANOVA was per-
formed to assess if there were differences in the alpha peak
positions between groups. The results are reported in detail in
Table 2, showing no significant differences of the spectral alpha
peak position.
A detailed statistical analysis of GFP within the frequency bands
follows. Given that the individual alpha peak frequencies are not
different between groups (Table 2), possible GFP differences in
the frequency bands are not confounded by this factor.
Repeated measures ANOVA for the three groups of subjects
(FTD, AD, and NC), using as dependent variables the seven fre-
quency bands, revealed a highly significant group effect (Wilks
test; F = 2.4; df1 = 12; df2 = 104; p = 0.010).
Post-hoc comparisons of groups for each frequency band were
performed using a non-parametric randomization version of ANO-
VA with correction for multiple testing. Table 3 and Fig. 2 show
mean relative GFP for the FTD, AD, and NC groups. Post-hoc (Tu-
key) tests indicated that the GFP for AD was higher than that for
NC (corrected p = 0.005) in the delta band. In the alpha1 band,
the GFP for NC was higher than that for FTD (corrected
p = 0.014). And, the GFP for FTD was higher than that for AD (cor-
rected p = 0.014) in the beta1 band.
Receiver operating characteristic (ROC) curves were analyzed
by means of the SPSS software. Based on the previous GFP analyses,
the quality of separation between groups were based on the delta
band GFP for AD and NC, alpha1 band GFP for FTD and NC, and
beta1 band GFP for FTD and AD. Table 4 shows a detailed summary
of ROC parameters and statistics. The areas under the curves in all
three discrimination cases are significantly different from chance,
corresponding to moderate accuracy in separation.
In addition, we performed two stepwise multiple correlation
analyses, where the seven independent variables were the relative
GFP values for each frequency band. In one case, the dependent
variable was the MMSE score, and in the other case, the FAB score.
For the MMSE score, a positive significant correlation with beta1
GFP was found only for the AD group (p = 0.04). For the FAB score,
only the FTD group was tested, and no significant correlations were
found.
3.2. sLORETA
Fig. 3 compares current density images in Talairach space ob-
tained by sLORETA for the FTD and NC groups. Red areas corre-
spond to significantly higher activity in the FTD group, and
yellow areas correspond to significantly higher activity in the NC
group (p < 0.047, Log-F-ratio threshold = 0.344). In Fig. 4, in the al-
pha1 frequency band, NC showed strong activity in the medial
frontal gyrus and the frontal lobe.
Fig. 5 compares current density images for the AD and NC
groups. Blue areas correspond to significantly higher activity in
the AD group, and yellow areas correspond to significantly higher
activity in the NC group (p < 0.050, Log-F-ratio threshold = 0.186).
The solid line surrounds images in the frequency band which had
a significant difference of GFP between AD and NC. In Fig. 6, in

Table 3
Post-hoc comparisons of groups using non-parametric ANOVA with randomization and correction for multiple testing.

Relative value (%) FTD AD NC P value

FTD vs. NC AD vs. NC FTD vs. AD
delta 43.34 (7.63) 49.33 (11.4) 39.51 (7.27) 0.284 0.005* 0.172
theta 11.59 (4.40) 12.28 (3.91) 10.70 (2.81) 0.848 0.353 0.968
alpha1 15.58 (6.06) 17.73 (11.26) 25.4 (14.05) 0.014* 0.175 0.883
alpha2 8.68 (4.15) 6.35 (1.78) 8.51 (4.35) 1 0.096** 0.075**
beta1 15.77 (4.34) 11.78 (4.34) 13.36 (4.95) 0.275 0.636 0.014*
beta2 2.96 (2.44) 1.53 (0.93) 1.612 (0.91) 0.072** 0.993 0.056**
beta3 2.08 (2.64) 1.00 (0.79) 0.95 (0.56) 0.194 0.997 0.25

Standard deviation was in parentheses.

Frontotemporal dementia; FTD, Alzheimer’s disease; AD, normal control; NC.
*
p > 0.05.
**
P > 0.1.
1722 K. Nishida et al. / Clinical Neurophysiology 122 (2011) 1718–1725

Table 4
ROC curve analysis.

AUC p Value 95% CI Sensitivity Specificity

Lower Upper
FTD vs. NC alpha1 band 0.69 0.03 0.529 0.858 0.55 0.84
AD vs. NC delta band 0.78 0.002 0.637 0.928 0.74 0.73
FTD vs. AD beta1 band 0.74 0.011 0.586 0.898 0.74 0.63

AUC: area under the curve.

ROC: receiver operating-characteristic.
p Value: test for AUC = 0.5 (chance discrimination).
95% CI: confidence interval for AUC.
FTD: frontotemporal dementia, AD: Alzheimer’s disease; NC: normal control.

Fig. 3. Compares current density images in Talairach space obtained by sLORETA for the FTD and NC groups. Red areas correspond to significantly higher activity in the FTD
group, and yellow areas correspond to significantly higher activity in the NC group (p < 0.047, Log-F-ratio threshold = 0.344). (A: anterior, P: posterior, FTD: frontotemporal
dementia, AD: Alzheimer disease, NC: normal control).

Fig. 4. In the alpha1 frequency band, NC showed strong activity in the medial frontal gyrus and the frontal lobe.

Fig. 5. Compares current density images for the AD and NC groups. Blue areas correspond to significantly higher activity in the AD group, and yellow areas correspond to
significantly higher activity in the NC group (p < 0.050, Log-F-ratio threshold = 0.186). The solid line surrounds images in the frequency band which is revealed a significant
difference of GFP between AD and NC. (A: anterior, P: posterior, FTD: frontotemporal dementia, AD: Alzheimer disease, NC: normal control).
 K. Nishida et al. / Clinical Neurophysiology 122 (2011) 1718–1725 1723

Fig. 6. In the delta frequency band, activity was significantly higher for AD in widespread areas including the medial frontal gyrus and the frontal lobe, especially in the right
hemisphere.

Fig. 7. Compares current density images for FTD and AD. Red areas mean that activity was stronger than the baseline for FTD. Blue areas mean that activity was stronger than
the baseline for AD (p < 0.047, Log-F-ratio threshold = 0.280). The solid lines indicate images in frequency bands which has significant differences of GFP between FTD and AD.
(A: anterior, P: posterior, FTD: frontotemporal dementia, AD: Alzheimer disease, NC: normal control).

Fig. 8. In the beta1 band, FTD exhibited greater activity in parietal lobe and sensorimortar area.

the delta frequency band, activity was significantly higher for AD in
widespread areas including the medial frontal gyrus and the fron-
tal lobe, especially in the right hemisphere.
Fig. 7 compares current density images for FTD and AD. Red
areas correspond to significantly higher activity in the FTD group,
and blue areas correspond to significantly higher activity in the
AD group (p < 0.050, Log-F-ratio threshold = 0.280. The solid lines
indicate images in frequency band that had significant difference
of GFP between FTD and AD. In Fig. 8, in the beta1 frequency band,
activity was significantly higher for FTD in parietal lobe and senso-
rimotor area.
4. Discussion
In the present study, GFP analysis revealed significant group
effects in the delta, alpha1, and beta1 bands. In a subsequent
sLORETA analysis, significant differences in activity were ob-
served in the alpha1 frequency band (NC > FTD) in the orbital
frontal and temporal lobe, in the delta frequency band (AD > NC)
in widespread areas including the frontal lobe, and in the beta1
band (FTD > AD) in the parietal lobe and sensorimotor area.
These significant differences are sufficient for a moderate separa-
tion of the groups, as shown in the ROC-curve analyses (see e.g.
1724 K. Nishida et al. / Clinical Neurophysiology 122 (2011) 1718–1725
(Yuan et al., 2009) and (Lehmann et al., 2007) for comparative
values of ROC area values).
We found that the activity in the alpha1 band was significantly
higher for NC than for FTD. Our study partly agrees with Lindau et
al. (2003) finding that FTD has a tendency to exhibit a decrease in
the alpha (8.0–11.0 Hz) band. It should be noted that the frequency
bands used in this study (Kubicki et al., 1979) are not identical to
those used by Lindau et al. and comparisons should be viewed with
a certain amount of caution.
However, in the beta (12.0–23.5 Hz) band, we observed an in-
crease in activity for FTD, which is the opposite of the Lindau et
al. results. This discrepancy is difficult to understand. One possible
explanation is that our FTD patients are different from those of the
Lindau et al. study. For instance, we controlled that our subjects
have a CDR scale in the range 0.5–1.0, which was not controlled
by Lindau. Further evidence that proves the importance of taking
into account disease severity when comparing populations was
provided by Julin et al. (1995), where it was shown that only when
comparing patients with MMSE > 22, a significant difference was
found for less abnormal EEG changes in frontal lobe dementia
(FLD) as compared to AD. One might speculate that if the Lindau
et al. subjects were in a more advanced FTD state, these patients
probably had more pathological changes with accompanying
decreased beta activity. These same considerations apply to the
results of Yener et al. (1996), in which of the 13 FTD patients,
one was in very mild stage (CDR 0.5), six in mild stage (CDR 1), 5
in moderate stage (CDR 2), and 1 in severe stage (CDR 3).
Using sLORETA to compare FTD and NC, we found significantly
lower alpha1 activity for FTD in frontal lobes, particularly in the
medial frontal gyrus. Seeley found gray matter atrophy in similar
regions in FTD patients (Seeley et al., 2008). Our results are consis-
tent with these findings, especially when considering that in gen-
eral, metabolism in basal prefrontal cortex correlates directly
with alpha band power (Sadato et al., 1998). The overlap of these
different imaging modalities in detecting pathological activity in
the same brain areas lends validation to the new non-invasive
imaging method sLORETA.
The GFP of the delta (1.5–6.0 Hz) band activity was higher for
the AD group than for the NC group. Taking into account that our
wide delta band includes the more popular definition from 1 to
3.5 Hz for delta, and that it overlaps with the popular definition
of the theta band (4–7.5 Hz), our results show a very good agree-
ment with those of Huang et al. (2000) and Lindau et al. (2003).
A positive significant correlation between MMSE score and
beta1 GFP was observed in the AD group. This result is consistent
with the decreased beta1 activity for the AD group when compared
to normal controls. In other words, the AD subjects have different
degrees of memory and general cognitive deficits, with the more
severe ones having the least beta1 activity, which is pathologically
lower than the normal group. Our results are in agreement with
those of Claus et al. (1998) where it was shown that lower pari-
eto-occipital beta was significantly associated with more decline
in global cognitive function.
Using sLORETA to compare AD and NC, we found that for AD
patients, the current density of the delta band increased in frontal,
temporal, and occipital regions. Previous results reported by
Babiloni et al. (2007) show that AD patients exhibit a widespread
increase in the amplitude of delta (2–4 Hz) in temporal and occip-
ital regions. In distinction from the results of Babiloni et al. we
observed significant increase of delta generators in frontal regions,
which would implicate a frontal lobe dysfunction in AD. These
findings are consistent with those of O’Brien et al. (1992), where
evidence is provided suggesting that frontal changes can occur
early in the course of Alzheimer’s disease.
The FTD group exhibited stronger beta1 band activity than the
AD group, both for GFP and for the intracranial electrical generators
(sLORETA) in the parietal lobe and sensorimotor areas. Other studies
that present evidence in favor of these results are discussed below.
Du et al. (2007) reported in an MRI study that AD patients had
thinner cortex in parts of bilateral parietal and precuneus regions
compared to FTD. In a similar comparative study by Du et al.
(2006) but using arterial spin labeling MRI, it was shown that
FTD was associated with higher perfusion bilaterally in inferior
parietal cortex than AD. Both these structural and functional differ-
ences might explain the decreased beta1 activity for the AD group.
Other studies that also show decreased function in parietal regions
for AD patients compared to FTD are reported (Varrone et al., 2002;
Foster et al., 2007).
In particular, with respect to the observed increase in beta gen-
erators for the FTD patients in sensorimotor areas, this result cor-
responds to a concomitant decrease in regional cerebral blood flow
that has been observed by Oishi et al. (2007) in the sensorimotor
areas. They found significant negative correlation between sensori-
motor EEG rhythm in the 10–20 Hz range with sensorimotor rCBF.
In addition, also supporting these findings, Lojkowska et al. (2002)
reported the motor cortex as one of the regions with significant
hypoperfusion in FTD as compared to mild AD.
From another point of view, the higher beta current density
exhibited by FTD patients as compared with AD patients may be
the cause of the difference between the main symptoms of FTD
and AD (Pijnenburg et al., 2004). Specifically, various somatic
symptoms persist in FTD patients, which is likely associated to
the high current density of beta1 waves in the sensorimotor area,
thus giving rise to the physical symptoms of FTD, in agreement
with Poprawski et al. (2007).
5. Limitations and outlook
One limitation of this study is the use of only 19 electrodes,
which is relatively small for localization. However, it should be
emphasized that this does not necessarily imply mislocalization,
but rather it decreases the spatial resolution. For instance, using
as few as 19 or 27 electrodes, Winterer et al. (2001) and Mulert
et al. (2004) have provided cross-modal validation for LORETA
across many different Brodmann areas. Accordingly, the localiza-
tion results in this study consist of wide-spread cortical areas, as
should be expected in the case of the pathologies studied here,
which affect widely distributed brain areas.
The present study suffers from two further limitations. The
number of patients was small; and we could not conduct a neuro-
pathological examination, which is usually necessary to make a
definitive diagnosis. Further study is needed to compare patient
groups according to the stage of the disease and the type of symp-
toms and to investigate whether or not there is a correlation be-
tween results obtained with quantative EEG and those obtained
with other tools, such as MRI, SPECT, and PET.
In summary, our results suggest that quantative EEG, including
sLORETA, provide information that is at least partially (although
not sufficiently) useful in distinguishing FTD from AD in the early
stages.
Acknowledgements
This project was sponsored by a grant from the Medical Re-
search Foundation for Senile Dementia of Osaka. We thank Misa
Suzuki for help in data collection.
References
Babiloni C, Cassetta E, Binetti G, Tombini M, Del Percio C, Ferreri F, et al. Resting EEG
sources correlate with attentional span in mild cognitive impairment and
Alzheimer’s disease. Eur J Neurosci 2007;12:3742–57.
 K. Nishida et al. / Clinical Neurophysiology 122 (2011) 1718–1725
Babiloni C, Frisoni GB, Pievani M, Vecchio F, Lizio R, Buttiglione M, et al.
Hippocampal volume and cortical sources of EEG alpha rhythms in mild
cognitive impairment and Alzheimer disease. Neuroimage 2009;1:123–35.
Babiloni C, Miniussi C, Moretti DV, Vecchio F, Salinari S, Frisoni G, et al. Cortical
networks generating movement-related EEG rhythms in Alzheimer’s disease:
an EEG coherence study. Behav Neurosci 2004;4:698–706.
Chan D, Walters RJ, Sampson EL, Schott JM, Smith SJ, Rossor MN. EEG abnormalities
in frontotemporal lobar degeneration. Neurology 2004;9:1628–30.
Claus J, Kwa V, Teunisse S, Walstra G, van Gool W, TM K. Slowing on quantitative
spectral EEG is a marker for rate of subsequent cognitive, functional decline in
early Alzheimer disease. Alzheimer Disease Assoc Disord 1998;3:167.
de Haan W, Pijnenburg YA, Strijers RL, van der Made Y, van der Flier WM, Scheltens
P, et al. Functional neural network analysis in frontotemporal dementia and
Alzheimer’s disease using EEG and graph theory. BMC Neurosci 2009; 101.
Dierks T, Ihl R, Frolich L, Maurer K. Dementia of the Alzheimer type: effects on the
spontaneous EEG described by dipole sources. Psychiatry Res 1993;3:151–62.
DSM-IV, A.P.A.T.F.o. DSM-IV: diagnostic and statistical manual of mental disorders,
1994.
Du A, Jahng G, Hayasaka S, Kramer J, Rosen H, Gorno-Tempini M, et al.
Hypoperfusion in frontotemporal dementia and Alzheimer disease by arterial
spin labeling MRI. Neurology 2006;7:1215.
Du A, Schuff N, Kramer J, Rosen H, Gorno-Tempini M, Rankin K, et al. Different
regional patterns of cortical thinning in Alzheimer’s disease and frontotemporal
dementia. Brain 2007.
Dubois B, Slachevsky A, Litvan I, Pillon B. The FAB: a frontal assessment battery at
bedside. Neurology 2000;11:1621.
Folstein MF, Folstein SE, McHugh PR. Mini-mental state. A practical method for
grading the cognitive state of patients for the clinician. J Psychiatr Res
1975;3:189–98.
Foster NL, Heidebrink JL, Clark CM, Jagust WJ, Arnold SE, Barbas NR, et al. FDG-PET
improves accuracy in distinguishing frontotemporal dementia and Alzheimer’s
disease. Brain 2007;10:2616–35.
Frackowiak R. Human brain function. Academic Press; 2004.
Fuchs M, Kastner J, Wagner M, Hawes S, Ebersole J. A standardized boundary
element method volume conductor model. Clin Neurophysiol 2002;5:702–12.
Huang C, Wahlund L, Dierks T, Julin P, Winblad B, Jelic V. Discrimination of
Alzheimer’s disease and mild cognitive impairment by equivalent EEG sources:
a cross-sectional and longitudinal study. Clin Neurophysiol 2000;11:1961–7.
Hughes CP, Berg L, Danziger WL, Coben LA, Martin RL. A new clinical scale for the
staging of dementia. Br J Psychiatry 1982; 566–72.
Ishii K, Sakamoto S, Sasaki M, Kitagaki H, Yamaji S, Hashimoto M, et al. Cerebral
glucose metabolism in patients with frontotemporal dementia. J Nucl Med
1998;11:1875.
Julin P, Wahlund L, Basun H, Persson A, Måre K, Rudberg U. Clinical diagnosis of
frontal lobe dementia and Alzheimer fs disease relation to cerebral perfusion,
brain atrophy and electroencephalography. Dement Geriatr Cogn Disord
1995;3:142–7.
Jurcak V, Okamoto M, Singh A, Dan I. Virtual 10–20 measurement on MR images for
inter-modal linking of transcranial and tomographic neuroimaging methods.
NeuroImage 2005;4:1184–92.
Koenig T, Prichep L, Dierks T, Hubl D, Wahlund L, John E, et al. Decreased EEG
synchronization in Alzheimer’s disease and mild cognitive impairment.
Neurobiol Aging 2005;2:165–71.
Kubicki S, Herrmann WM, Fichte K, Freund G. Reflections on the topics: EEG
frequency bands and regulation of vigilance. Pharmakopsychiatr
Neuropsychopharmakol 1979;2:237–45.
Lancaster JL, Woldorff MG, Parsons LM, Liotti M, Freitas CS, Rainey L, et al.
Automated Talairach atlas labels for functional brain mapping. Hum Brain
Mapp 2000;3:120–31.
Lehmann C, Koenig T, Jelic V, Prichep L, John RE, Wahlund LO, et al. Application and
comparison of classification algorithms for recognition of Alzheimer’s disease in
electrical brain activity (EEG). J Neurosci Methods 2007;2:342–50.
Lehmann D, Skrandies W. Reference-free identification of components of
checkerboard-evoked multichannel potential fields⁄ 1. Electroencephalogr
Clin Neurophysiol 1980;6:609–21.
Lindau M, Jelic V, Johansson SE, Andersen C, Wahlund LO, Almkvist O. Quantitative
EEG abnormalities and cognitive dysfunctions in frontotemporal dementia and
Alzheimer’s disease. Dement Geriatr Cogn Disord 2003;2:106–14.
Lojkowska W, Ryglewicz D, Jedrzejczak T, Sienkiewicz-Jarosz H, Minc S, Jakubowska
T, et al. SPECT as a diagnostic test in the investigation of dementia. J Neurol Sci
2002; 215–19.
Luckhaus C, Grass-Kapanke B, Blaeser I, Ihl R, Supprian T, Winterer G, et al.
Quantitative EEG in progressing vs. stable mild cognitive impairment (MCI):
results of a 1-year follow-up study. Int J Geriatr Psychiatry 2008;11:
1148–55.
Mazziotta J, Toga A, Evans A, Fox P, Lancaster J, Zilles K, et al. A probabilistic atlas
and reference system for the human brain: international consortium for brain
mapping (ICBM). Philos Trans R Soc Lond B Biol Sci 2001;1412:1293–322.
1725
McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical
diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group
under the auspices of Department of Health and Human Services Task Force on
Alzheimer’s Disease. Neurology 1984;7:939–44.
Mioshi E, Bristow M, Cook R, Hodges JR. Factors underlying caregiver stress in
frontotemporal dementia and Alzheimer’s disease. Dement Geriatr Cogn Disord
2009;1:76–81.
Mosconi L, Tsui WH, Herholz K, Pupi A, Drzezga A, Lucignani G, et al. Multicenter
standardized 18F-FDG PET diagnosis of mild cognitive impairment, Alzheimer’s
disease, and other dementias. J Nucl Med 2008;3:390–8.
Mulert C, Jãger L, Schmitt R, Bussfeld P, Pogarell O, Möller H, et al. Integration of
fMRI and simultaneous EEG: towards a comprehensive understanding of
localization and time-course of brain activity in target detection. NeuroImage
2004;1:83–94.
Neary D, Snowden JS, Gustafson L, Passant U, Stuss D, Black S, et al. Frontotemporal
lobar degeneration: a consensus on clinical diagnostic criteria. Neurology
1998;6:1546–54.
Nichols T, Holmes A. Nonparametric permutation tests for functional
neuroimaging: a primer with examples. Hum Brain Mapp 2002;1:1–25.
O’Brien J, Eagger S, Syed G, Sahakian B, Levy R. A study of regional cerebral blood
flow and cognitive performance in Alzheimer’s disease. J Neurol Neurosurgery
Psychiatry 1992;12:1182.
Oguro H, Yamaguchi S, Abe S, Ishida Y, Bokura H, Kobayashi S. Differentiating
Alzheimer fs disease from subcortical vascular dementia with the FAB test. J
Neurol 2006;11:1490–4.
Oishi N, Mima T, Ishii K, Bushara KO, Hiraoka T, Ueki Y, et al. Neural correlates of
regional EEG power change. NeuroImage 2007;4:1301–12.
Park YM, Che HJ, Im CH, Jung HT, Bae SM, Lee SH. Decreased EEG synchronization
and its correlation with symptom severity in Alzheimer’s disease. Neurosci Res
2008;2:112–7.
Pascual-Marqui RD. Standardized low-resolution brain electromagnetic
tomography (sLORETA): technical details. Methods Find Exp Clin Pharmacol
2002:5–12.
Passant U, Rosen I, Gustafson L, Englund E. The heterogeneity of frontotemporal
dementia with regard to initial symptoms, qEEG and neuropathology. Int J
Geriatr Psychiatry 2005;10:983–8.
Pijnenburg Y, Gillissen F, Jonker C, Scheltens P. Initial complaints in frontotemporal
lobar degeneration. Dement Geriatr Cogn Disord 2004;4:302–6.
Poprawski TJ, Pluzyczka AN, Park Y, Chennamchetty VN, Halaris A, Crayton JW, et al.
Multimodality imaging in a depressed patient with violent behavior and
temporal lobe seizures. Clin EEG Neurosci 2007;3:175–9.
Rossini PM, Del Percio C, Pasqualetti P, Cassetta E, Binetti G, Dal Forno G, et al.
Conversion from mild cognitive impairment to Alzheimer’s disease is predicted
by sources and coherence of brain electroencephalography rhythms.
Neuroscience 2006;3:793–803.
Sadato N, Nakamura S, Oohashi T, Nishina E, Fuwamoto Y, Waki A, et al. Neural
networks for generation and suppression of alpha rhythm: a PET study.
Neuroreport 1998;5:893.
Seeley WW, Crawford R, Rascovsky K, Kramer JH, Weiner M, Miller BL, et al. Frontal
paralimbic network atrophy in very mild behavioral variant frontotemporal
dementia. Arch Neurol 2008;2:249–55.
Varrone A, Pappat S, Carac C, Soricelli A, Milan G, Quarantelli M, et al. Voxel-based
comparison of rCBF SPET images in frontotemporal dementia and Alzheimer’s
disease highlights the involvement of different cortical networks. Eur J Nucl
Med Mol Imag 2002;11:1447–54.
Waragai M, Mizumura S, Yamada T, Matsuda H. Differentiation of early-stage
Alzheimer’s disease from other types of dementia using brain perfusion single
photon emission computed tomography with easy Z-score imaging system
analysis. Dement Geriatr Cogn Disord 2008;6:547–55.
Winterer G, Mulert C, Mientus S, Gallinat J, Schlattmann P, Dorn H, et al. P300 and
LORETA: comparison of normal subjects and schizophrenic patients. Brain
Topogr 2001;4:299–313.
Yener GG, Leuchter AF, Jenden D, Read SL, Cummings JL, Miller BL. Quantitative EEG
in frontotemporal dementia. Clin Electroencephalogr 1996;2:61–8.
Yoland AL, Strijers R, Made Y, Van der Flier W, Scheltens P, Stam C. Investigation of
resting-state EEG functional connectivity in frontotemporal lobar degeneration.
Clin Neurophysiol 2008;8:1732–8.
Yoshimura M, Isotani T, Yagyu T, Irisawa S, Yoshida T, Sugiyama M, et al. Global
approach to multichannel electroencephalogram analysis for diagnosis and
clinical evaluation in mild Alzheimer’s disease. Neuropsychobiology
2004;3:163–6.
Young K, Du AT, Kramer J, Rosen H, Miller B, Weiner M, et al. Patterns of structural
complexity in Alzheimer’s disease and frontotemporal dementia. Hum Brain
Mapp 2009;5:1667–77.
Yuan Y, Gu Z, Wei W. Fluorodeoxyglucose-positron-emission tomography, single-
photon emission tomography, structural MR imaging for prediction of rapid
conversion to Alzheimer disease in patients with mild cognitive impairment: a
meta-analysis. Am J Neuroradiol 2009;2:404.