Quantitative EEG Markers in Mild Cognitive Impairment: Degenerative versus Vascular Brain ...

13 Pages·2014·1.31 MB·English

HindawiPublishingCorporation
InternationalJournalofAlzheimer’sDisease
Volume2012,ArticleID917537,12pages
doi:10.1155/2012/917537
Review Article
Quantitative EEG Markers in Mild Cognitive Impairment:
Degenerative versus Vascular Brain Impairment
D.V.Moretti,O.Zanetti,G.Binetti,andG.B.Frisoni
CentroSanGiovannidiDioFatebenefratelli,TRccs,25125Brescia,Italy
CorrespondenceshouldbeaddressedtoD.V.Moretti,[email protected]
Received28November2011;Revised17May2012;Accepted21May2012
AcademicEditor:SeishiTerada
Copyright©2012D.V.Morettietal.ThisisanopenaccessarticledistributedundertheCreativeCommonsAttributionLicense,
whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycited.
Weevaluatedtherelationshipbetweenbrainrhythmicityandboththecerebrovasculardamage(CVD)andamygdalohippocampal
complex(AHC)atrophy,asrevealedbyscalpelectroencephalography(EEG)inacohortofsubjectswithmildcognitiveimpairment
(MCI).AllMCIsubjectsunderwentEEGrecordingandmagneticresonanceimaging.EEGswererecordedatrest.Relativepower
wasseparatelycomputedfordelta,theta,alpha1,alpha2,andalpha3frequencybands.Inthespectralbandpowertheseverityof
CVDwasassociatedwithincreaseddeltapoweranddecreasedalpha2power.Noassociationofvasculardamagewasobservedwith
alpha3power.Moreover,thetheta/alpha1ratiocouldbeareliableindexfortheestimationoftheindividualextentofCVdamage.
On the other side, the group with moderate hippocampal atrophy showed the highest increase of alpha2 and alpha3 power.
Moreover, when the amygdalar and hippocampal volumes are separately considered, within amygdalohippocampal complex
(AHC),theincreaseoftheta/gammaratioisbestassociatedwithamygdalaratrophywhereasalpha3/alpha2ratioisbestassociated
withhippocampalatrophy.CVDandAHCdamagesareassociatedwithspecificEEGmarkers.Sofar,theseEEGmarkerscould
haveaprospectivevalueindifferentialdiagnosisbetweenvascularanddegenerativeMCI.
1.Introduction temporal lobe (MTL) activations in MCI subjects versus
controls,duringtheperformanceofmemorytasks[16,17].
Mild cognitive impairment (MCI) is a clinical state inter- Nonetheless, fMRI findings in MCI are discrepant, as MTL
mediate between elderly normal cognition and dementia hypoactivation similar to that seen in AD patients [18]
that affects a significant amount of the elderly population, has also been reported [19]. Recent postmortem data from
featuringmemorycomplaintsandcognitiveimpairmenton subjects—whohadbeenprospectivelyfollowedandclinically
neuropsychologicaltesting,butnodementia[1–3]. characterizeduptoimmediatelybeforetheirdeath—indicate
The hippocampus is one of the first and most affected thathippocampalcholineacetyltransferaselevelsarereduced
brainregionsimpactedbybothAlzheimer’sdiseaseandmild in Alzheimer’s dementia, but in fact they are upregulated
cognitive impairment (MCI; [4–9]). In mild-to-moderate in MCI [15], presumably because of reactive upregulations
Alzheimer’s disease patients, it has been shown that hip- of the enzyme activity in the unaffected hippocampal
pocampal volumes are 27% smaller than in normal elderly cholinergicaxons.PreviousEEGstudies[20–26]haveshown
controls[10,11],whereaspatientswithMCIshowavolume a decrease—ranging from 8 to 10.5Hz (low alpha)—of
reduction of 11% [11]. So far, from a neuropathological the alpha frequency power band in MCI subjects, when
point of view, the progression of disease from MCI state to comparedtonormalelderlycontrols[20,27–30].However,a
later stages seems to follow a linear course. Nevertheless, recentstudyhasshownanincrease—rangingfrom10.5to13
there is some evidence from functional [12–14] and bio- Hz(highalpha)—ofthealphafrequencypowerband,onthe
chemical studies [15] that the process of conversion from occipitalregioninMCIsubjects,whencomparedtonormal
nondemented to clinically evident demented state is not so elderlyandADpatients[30].Thesesomewhatcontradictory
linear.RecentfMRIstudieshavesuggestedincreasedmedial findings may be explained by the possibility that MCI
2 InternationalJournalofAlzheimer’sDisease
subjectshavedifferentpatternsofplasticorganizationduring 2.MaterialsandMethods
the disease and that the activation (or hypoactivation)
of different cerebral areas is based on various degrees of 2.1.Subjects
hippocampal atrophy. If this hypothesis is true, then EEG
2.1.1. General Considerations about Recruitment. All the
changes of rhythmicity have to occur nonproportionally to
subjects in the study were recruited from the same cohort
the hippocampal atrophy, as previously demonstrated in a
intheMemoryClinicoftheScientificInstituteforResearch
studyofauditoryevokedpotentials[31].
and Care (IRCCS) of Alzheimer’s and psychiatric diseases
Inarecentstudy[32],theresultsconfirmthehypothesis
“Fatebenefratelli”inBrescia,Italy.Allexperimentalprotocols
thattherelationshipbetweenhippocampalvolumeandEEG
hadbeenapprovedbythelocalEthicsCommittee.Informed
rhythmicityisnotproportionaltothehippocampalatrophy,
consent was obtained from all participants or their care-
asrevealedbytheanalysesofboththerelativebandpowers
givers,accordingtotheCodeofEthicsoftheWorldMedical
and the individual alpha markers. Such a pattern seems
Association(DeclarationofHelsinki).Thedifferenceinthe
to emerge because, rather than a classification based on
clinicalparameters,discretehippocampalvolumedifferences size of the populations (cerebrovascular and degenerative
(about1cm3)areanalyzed.Indeed,thegroupwithmoderate impairment) is due to technical reasons linked to the MRI
analysis.
hippocampal atrophy showed the highest increase in the
thetapoweronfrontalregionsandofthealpha2andalpha3
powersonfrontalandtemporoparietalareas. Cerebrovascular Impairment. For the present study, 99 sub-
Recently, two specific EEG markers, theta/gamma and jects with MCI were recruited. Table1 shows the main
alpha3/alpha2frequencyratio,havebeenreliablyassociated featuresofthisgroup.
with the atrophy of amygdalo-hippocampal complex [33],
as well as with memory deficits, which are a major risk
DegenerativeImpairment. Forthepresentstudy,79subjects
for the development of AD in MCI subjects [34]. Based on
withMCIwererecruited.Table3showsthemaincharacter-
the tertiles values of decreasing AHC volume, three groups
isticsofthegroup.
of AHC growing atrophy were obtained. AHC atrophy is
associated with memory deficits as well as with increase
of theta/gamma and alpha3/alpha2 ratio. Moreover, when 2.2.SharedProcedures
the amygdalar and hippocampal volumes are separately
2.2.1. EEG Recordings. All recordings were obtained in the
considered, within AHC, the increase of theta/gamma
morning with subjects resting comfortably. Vigilance was
ratio is best associated with amygdalar atrophy whereas
continuouslymonitoredinordertoavoiddrowsiness.
alpha3/alpha2 ratio is best associated with hippocampal
The EEG activity was recorded continuously from 19
atrophy.
sites by using electrodes set in an elastic cap (Electro-Cap
The role of cerebrovascular (CV) disease and ischemic
International, Inc.) and positioned according to the 10–
brain damage in cognitive decline remains controversial.
20 International system (Fp1, Fp2, F7, F3, Fz, F4, F8, T3,
Although not all patients with mild cognitive impairment
C3, Cz, C4, T4, T5, P3, Pz, P4, T6, O1, and O2). The
due to CV damage develop a clinically defined dementia,
groundelectrodewasplacedinfrontofFz.Theleftandright
all such patients are at risk and could develop dementia
mastoidsservedasreferenceforallelectrodes.Therecordings
in the 5 years following the detection of cognitive decline.
were used off line to rereference the scalp recordings to
Cognitive impairment due to subcortical CV damages is
the common average. Data were recorded with a band-
thoughttobecausedbyfocalormultifocallesionsinvolving
pass filter of 0.3–70Hz and digitized at a sampling rate of
strategicbrainareas.Theselesionsinbasalganglia,thalamus,
250Hz (BrainAmp, BrainProducts, Germany). Electrodes-
or connecting white matter induce interruption of thala-
skinimpedancewassetbelow5kΩ.Horizontalandvertical
mocortical and striatocortical pathways. As a consequence,
deafferentation of frontal and limbic cortical structures is eyemovementsweredetectedbyrecordingtheelectrooculo-
gram(EOG).Therecordinglasted5minutes,withsubjects
produced.Thepatternofcognitiveimpairmentisconsistent
withclosedeyes.Longerrecordingswouldhavereducedthe
with models of impaired cortical and subcortical neuronal
variability of the data, but they would also have increased
pathways [36]. Even when CV pathology appears to be
the main underlying process, the effects of the damaged thepossibilityofslowingofEEGoscillationsduetoreduced
vigilance and arousal. EEG data were then analyzed and
brain parenchyma are variable and, therefore, the clinical,
fragmentedofflineinconsecutiveepochsof2seconds,with
radiological, and pathological appearances may be hetero-
a frequency resolution of 0.5Hz. The average number of
geneous.Aneurophysiologicalapproachcouldbehelpfulin
differentiating structural from functional CV damage [35]. epochsanalyzedwas140rangingfrom130to150.TheEEG
epochs with ocular, muscular, and other types of artifacts
The quantitative analysis of electroencephalographic (EEG)
werediscarded.
rhythms in resting subjects is a low-cost but still powerful
approach to the study of elderly subjects in normal aging,
MCI, and dementia. The aim of this study was to compare 2.2.2.AnalysisofIndividualFrequencyBands. AdigitalFFT-
specific EEG markers that could be useful for diagnostic based power spectrum analysis (Welch technique, Hanning
andprognosticpurposeintheinvestigationofpatientswith windowing function, no phase shift) computed—ranging
cognitivedecline. from 2 to 45Hz—the power density of EEG rhythms with
InternationalJournalofAlzheimer’sDisease 3
Table1:Meanvalues±standarderrorofdemographiccharacteristics,neuropsychologicalandARWMCscoresoftheMCIsubgroups.F/M:
female/male.Ageandeducationareexpressedinyears.Group1:novasculardamage;group2:mildvasculardamage;group3:moderate
vasculardamage;group4:severevasculardamage.
Group1 Group2 Group3 Group4
Subjects(f/m) 27(18/9) 41(31/10) 19(10/9) 12(9/3)
Age 70.1(±1.7) 69.9(±1.1) 69.7(±1.9) 70.5(±2.4)
Education 7.1(±0.7) 7(±0.6) 7(±0.9) 10(±1.6)
MMSE 26.7(±0.4) 26.5(±0.4) 27(±0.4) 26.1(±0.7)
ARWMCscale 0 1–5 6–10 11–15
a 0.5Hz frequency resolution. Methods are exposed in subjectedtodiagnosticneuroimagingprocedures(magnetic
detailelsewhere[32,35,37].Briefly,twoanchorfrequencies resonanceimaging(MRI))andlaboratorybloodanalysisto
were selected according to the literature guidelines [38], ruleoutothercausesofcognitiveimpairment.
that is, the theta/alpha transition frequency (TF) and the The present inclusion and exclusion criteria for MCI
individualalphafrequency(IAF)peak.BasedonTFandIAF, were based on previous seminal studies [2, 3, 43–46].
we estimated the following frequency band range for each Inclusion criteria in the study were all of the following: (i)
subject: delta, theta, low alpha band (alpha1 and alpha2), complaintbythepatientorreportbyarelativeorthegeneral
andhighalphaband(alpha3).Moreover,individualbetaand practitionerofmemoryorothercognitivedisturbances;(ii)
gamma frequencies were computed. Three frequency peaks Mini-Mental State Examination (MMSE; [39]) score of 24
were detected in the frequency range from the individual to 27/30 or MMSE of 28 and higher plus low performance
alpha 3 frequency band and 45Hz. These peaks were (score of 2/6 or higher) on the clock drawing test [47];
named beta 1 peak (IBF 1), beta 2 peak (IBF 2), and (iii) sparing of instrumental and basic activities of daily
gamma peak (IGF). Based on peaks, the frequency ranges living or functional impairment stably due to causes other
were determined. Beta1 ranges from alpha 3 to the lower than cognitive impairment, such as physical impairments,
spectralpowervaluebetweenbeta1andbeta2peak;beta2 sensory loss, and gait or balance disturbances. Exclusion
frequency ranges from beta 1 to the lower spectral power criteria were any one of the following: (i) age of 90 years
value between beta 2 and gamma peak; gamma frequency andolder;(ii)historyofdepressionorpsychosisofjuvenile
ranges from beta 2 to 45Hz, which is the end of the onset;(iii)historyorneurologicalsignsofmajorstroke;(iv)
range considered. The frequency range was determined for other psychiatric diseases, epilepsy, drug addiction, alcohol
each patient. On average, the boundaries of the frequency dependence;(v)useofpsychoactivedrugsincludingacetyl-
bands were as follows: delta 2.9–4.9Hz; theta 4.9–6.9Hz; cholinesterase inhibitors or other drugs enhancing brain
alpha16.9–8.9Hz;alpha28.9–10.9Hz;alpha310.9–12-9Hz; cognitivefunctions;(vi)currentorpreviousuncontrolledor
beta112,9–19,2Hz;beta219.2–32.4;gamma32.4–45.Inthe complicated systemic diseases (including diabetes mellitus)
frequency bands determined in this way, the relative power ortraumaticbraininjuries.
spectraforeachsubjectwerecomputed.Therelativepower All patients underwent (i) semistructured interview
density for each frequency band was computed as the ratio with the patient and—whenever possible—with another
between the absolute power and the mean power spectra informant (usually the patient’s spouse or a child) by a
from2to45Hz.Finally,thetheta/gammaandalpha3/alpha2 geriatrician or neurologist; (ii) physical and neurological
relative power ratio were computed and analyzed. The examinations;(iii)performance-basedtestsofphysicalfunc-
analysis of other frequencies was not in the scope of this tion, gait, and balance; (iv) neuropsychological assessment
study. evaluating verbal and nonverbal memory, attention, and
executive functions (Trail Making Test B-A; Clock Drawing
Test; [47, 48]), abstract thinking (Raven matrices; [49]),
2.2.3. Diagnostic Criteria. In this study we enrolled sub- frontalfunctions(InvertedMotorLearning;[50]),language
jects afferents to the Scientific Institute of Research and (Phonological and Semantic fluency; Token test; [51]), and
Care Fatebenefratelli in Brescia, Italy. Patients were taken apraxia and visuoconstructional abilities (Rey figure copy;
from a prospective project on clinical progression of MCI. [52]);(v)assessmentofdepressivesymptomswiththeCenter
The project was aimed to study the natural history of for Epidemiologic Studies Depression Scale (CES-D; [53]).
nondemented persons with apparently primary cognitive Giventheaimofthestudytoevaluatetheimpactofvascular
deficits, not caused by psychic (anxiety, depression, etc.) damageonEEGrhythms,inthisstudywedidnotconsider
or physical (uncontrolled heart disease, uncontrolled dia- theclinicalsubtypeofMCI,thatis,amnesic,nonamnesic,or
betes, etc.) conditions. Patients were rated with a series multipledomain.
of standardized diagnostic tests, including the Mini-Mental
State Examination (MMSE; [39]), the Clinical Dementia
Rating Scale (CDRS; [40]), the Hachinski Ischemic Scale 2.2.4. Magnetic Resonance Imaging (MRI) and CV Damage
(HIS; [41]), and the Instrumental and Basic Activities of Evaluation. Magneticresonance(MR)imageswereacquired
DailyLiving(IADL,BADL,[42]).Inaddition,patientswere using a 1.0 Tesla Philips Gyroscan. Axial T2 weighted,
4 InternationalJournalofAlzheimer’sDisease
protondensity(DP),andfluidattenuatedinversionrecovery Plot of means P
Delta
(FLAIR)imageswereacquiredwiththefollowingacquisition 2-way interaction P Alpha 2
parameters:TR=2000ms,TE=8.8/110ms,flipangle=90◦, F(12.38)=2.6;P<0.0025
4.5
field of view = 230mm, acquisition matrix 256×256, slice P<0.0007
thickness5mmforT2/DPsequencesandTR=5000ms,TE 4 G1 versus G3
=100ms,flipangle=90◦,fieldofview=230mm,acquisition
matSriuxb2c5o6rt×ica2l5c6e,rselbicreovthasicckunlaerssd5ismeamsef(osCrVFLDA)IwRaismaasgseess.sed ensity 3.53
d
using the rating scale for age-related white matter change er
(ARWMC) on T2-weighted and FLAIR MR images. White ow 2.5 P=0.05
p
matter changes (WMC) was rated by a single observer al G1 versus G4
(R.R.)intherightandlefthemispheresseparatelyinfrontal, ectr 2 P<0.00003
p
parietooccipital,temporal,andinfratentorialareasandbasal S 1.5 G1 versus G4
ganglia on a 4-point scale. The observer of white matter
1
changeswasblindtotheclinicalinformationofthesubjects.
Subscoresof0,1,2,and3wereassignedinfrontal,parieto- 0.5
occipital, temporal, and infratentorial areas for no WMC, Delta Theta Alpha 1 Alpha 2 Alpha 3
focal lesions, beginning confluence of lesions, and diffuse Frequency bands
involvement of the entire region, respectively. Subscores of
Group 1 Group 3
0,1,2,and3wereassignedinbasalgangliafornoWMC,1
Group 2 Group 4
focallesion,morethan1focallesion,andconfluentlesions,
respectively. Total score was the sum of subscores for each Figure1:StatisticalANOVAinteractionamonggroups,factorand
relative band power (delta, theta, alpha1, alpha2, and alpha3). In
area in the left and right hemisphere, ranging from 0 to
thediagramthedifferenceindeltaandalpha2poweramonggroups
30. As regards the ARWMC scale, the interrater reliability,
as calculated with weighted k value, was 0.67, indicative of isalsoindicated,basedonDuncan’sposthoctesting.G1,group1:
novasculardamage;G2,group2:mildvasculardamage;G3,group
moderate agreement [54]. We assessed test-retest reliability
3:moderatevasculardamage;G4,group4:severevasculardamage
onarandomsampleof20subjects.Theintraclasscorrelation
[32,35].
coefficient was 0.98, values above 0.80 being considered
indicativeofgoodagreement.
BasedonincreasingsubcorticalCVdamage,the99MCI
subjectsweresubsequentlydividedin4subgroupsalongthe
performed statistical analyses to evaluate the specificity of
rangebetweentheminimumandmaximumARWMCscore
thefollowingratios:theta/alpha1,usingascovariatealsoTF;
(resp. 0 and 15). In order to have the higher sensibility to
alpha2/alpha3usingascovariatealsoIAFandalpha1/alpha2
the CV damage, the first group was composed by subjects
withbothTFandIAFascovariate.Moreover,weperformed
withscore=0.Theothergroupswerecomposedaccordingto
correlations (Pearson’s moment correlation) between CV
equalrangeARWMCscores.Asaconsequence,weobtained
damagescoreandfrequencymarkers(TFandIAF),spectral
thefollowinggroups:group1(G1):novasculardamage,CV
power,andMMSE.Finally,weperformedacontrolstatistical
score 0; group 2 (G2): mild vascular damage, CV score 1–
analysis with 4 frequency bands, considering alpha1 and
5;group3(G3):moderatevasculardamage,CVscore6–10;
alpha2assingleband(lowalpha).Thisanalysishadtheaim
group4(G4):severevasculardamage,CVscore11–15.
ofverifyingifthelowalpha,whenconsideredasawhole,has
Table1 reports the mean values of demographic and
thesamebehavior.
clinicalcharacteristicsofthe4subgroups.
3.Results
2.2.5. Statistical Analysis. Preliminarily, any significant dif-
ference between groups in demographic variables, age, 3.1.VascularMCI. Figure1displaystheresultsforANOVA
education, and gender as well as MMSE score was taken analysis of these data showing a significant interaction
intoaccount.Onlyeducationshowedasignificantdifference between group and Band factors (F(12.380) = 2.60;P <
betweengroups(P<0.03).Foravoidingconfoundingeffect, 0.002). Interestingly, Duncan’s post hoc testing showed a
subsequent statistical analyses of variance (ANOVA) were significant higher delta power in G4 compared to G1 (P <
carriedoutusingage,education,gender,andMMSEscoreas 0.050)andasignificanthigheralpha2powerinG1compared
covariates.Duncan’stestwasusedforposthoccomparisons. to G3 and G4 (P < 0.000). On the contrary, no differences
ForallstatisticalteststhesignificancewassettoP<0.05. were found in theta, alpha1, and alpha 3 band powers.
A second session of ANOVA was performed on EEG Moreover,acloserlookatthedata,inrespecttothealpha1
relative power data. In this analysis, group factor was the frequency, showed a decrease proportional to the degree
independent variable and frequency band power (delta, of CV damage very similar to alpha2 band, although not
theta,alpha1,alpha2,andalpha3)thedependentvariable. significant. On the contrary, in the alpha3 band power this
As successive step, to evaluate the presence of EEG trendwasnotpresent,suggestingthatvasculardamagehad
indexes that correlate specifically with vascular damage, we noimpactonthisfrequencyband.
InternationalJournalofAlzheimer’sDisease 5
Table2:Meanvalues±standarderroroftheta/alpha1,alpha1/alpha2,andalpha2/alpha3ratiosintheMCIsubgroups.Group1:novascular
damage;group2:mildvasculardamage;group3:moderatevasculardamage;group4:severevasculardamage.
Group1 Group2 Group3 Group4
θ/α1 0.7(±0.05) 0.77(±0.05) 1.17(±0.05) 1.39(±0.14)
α1/α2 0.46(±0.03) 0.5(±0.03) 0.53(±0.05) 0.47(±0.04)
α2/α3 1.27(±0.12) 1.16(±0.1) 0.85(±0.05) 0.79(±0.07)
Table 3: Mean values ± standard deviation of sociodemographic characteristics, MMSE scores, white matter hyperintensities, and
hippocampal and amygdalar volume measurements. Hippocampal and amygdalar volumes refer to the whole amygdalohippocampal
complex(AHC)andaresingularlyconsidered(individual).Thet-testreferstoAHCversusindividualvolumeineachgroup.
MCIcohort Group1 Group2 Group3 Pvalue(ANOVA)
Numberofsubjects(f/m) 79(42/37) 27(14/13) 27(15/12) 25(13/12)
Age(years) 69.2±2.3 66.8±6.8 69.4±8.7 71.5±6.9 0.1
Education(years) 7.7±0.8 8.3±4.5 6.7±3.1 8.2±4.6 0.2
MMSE 27.1±0.4 27.5±1.5 27.4±1.5 26.6±1.8 0.1
TotalAHCvolume 6965.3±1248.8 8151.2±436.4 7082.7±266.9 5661.8±720.4 0.00001
AHC-hippocampalvolume(mm3) 4891.7±902.6 5771.6±361.1 4935.6±380.9 3967.9±650.3 0.00001
AHC-amygdalarvolume(mm3) 2073.5±348.7 2379.6±321.3 2147.1±301.3 1693.9±288.5 0.0001
Individualhippocampalvolume(mm3) 4889.8±962.4 5809.6±314.2 4969.4±257.6 3890.1±551.4 0.00001
Individualamygdalarvolume(mm3) 2071.7±446.4 2514.4±259.5 2079.2±122.8 1621.6±185.2 0.0001
Whitematterhyperintensities(mm3) 3.8±0.5 3.2±2.8 4.2±3.8 4.1±3.6 0.7
The correlation analysis between CV score and spectral sequence (TR = 5000ms, TE = 100ms, flip angle = 90◦,
band power showed a significant positive correlation with fieldofview=230mm,acquisitionmatrix=256×256,and
delta power (r = 0.221;P < 0.03) a significant negative slicethickness=5mm).Hippocampal,amygdalar,andwhite
correlationwithalpha1(r = −0.312;P < 0.002)andalpha2 matterhyperintensities(WMHs)volumeswereobtainedfor
power (r=−0.363;P < 0.0003). The correlations between each subject. The hippocampal and amygdalar boundaries
CV score with theta power (r = 0.183;P = 0.07) and weremanuallytracedoneachhemispherebyasingletracer
alpha3 power (r = −0.002;P = 0.93) were not significant with the software program DISPLAY (McGill University,
aswellasthecorrelationbetweenCVscoreandMMSE(r = Montreal, Canada) on contiguous 1.5mm slices in the
−0.07;P=0.4). coronalplane.Theamygdalaisanolive-shapedmassofgray
Table2 displays the values of the theta/alpha1 and matter located in the superomedial part of the temporal
alpha2/alpha3 power ratio. The statistical analysis of the lobe,partlysuperiorandanteriortothehippocampus.The
theta/alpha1ratioshowedamaineffectofgroup(F(3.91)= startingpointforamygdalatracingwasatthelevelwhereitis
15.51;P < 0.000). Duncan’s post hoc testing showed a separated from the entorhinal cortex by intrarhinal sulcus,
significantincreaseofthetheta/alpha1ratiobetweenG1and or tentorial indentation, which forms a marked indent at
G2 in respect to G3 and G4 (P < 0.000). Moreover, the thesiteoftheinferiorborderoftheamygdala.Theuncinate
increase of this ratio was significant also between G3 and fasciculus, at the level of basolateral nuclei groups, was
G4 (P < 0.04). The statistical analysis of the alpha2/alpha3 considered as the anterior-lateral border. The amygdalo-
power ratio showed a main effect of group (F(3.91) = striatal transition area, which is located between lateral
4.60;P < 0.005). Duncan’s post hoc testing showed a amygdaloidnucleusandventralputamen,wasconsideredas
significant decrease of the ratio between G1 and G3 (P < theposterior-lateralborder.Theposteriorendofamygdaloid
0.02),G1andG4(P<0.010),andG2andG4(P<0.05).The nucleus was defined as the point where gray matter starts
statisticalanalysisofthealpha1/alpha2ratiodidnotshowthe to appear superior to the alveolus and lateral to the
maineffectofgroup(P<0.2). hippocampus. If the alveolus was not visible, the inferior
horn of the lateral ventricle was employed as border [33].
The starting point for hippocampus tracing was defined
3.2. MRI Scans and Amygdalohippocampal Atrophy Evalu- as the hippocampal head when it first appears below the
ation. MRI scans were acquired with a 1.0 Tesla Philips amygdala, the alveus defining the superior and anterior
GyroscanattheNeuroradiologyUnitoftheCitta` diBrescia border of the hippocampus. The fimbria was included in
Hospital, Brescia. The following sequences were used to the hippocampal body, while the grey matter rostral to the
measure hippocampal and amygdalar volumes: a high- fimbriawasexcluded.Thehippocampaltailwastraceduntil
resolution gradient echo T1-weighted sagittal 3D sequence itwasvisibleasanovalshapelocatedcaudallyandmedially
(TR = 20ms, TE = 5ms, flip angle = 30◦, field of view = tothetrigoneofthelateralventricles[32,35].Theintraclass
220mm,acquisitionmatrix=256×256,andslicethickness= correlation coefficients were 0.95 for the hippocampus and
1.3mm) and a fluid-attenuated inversion recovery (FLAIR) 0.83fortheamygdala.
6 InternationalJournalofAlzheimer’sDisease
White matter hyperintensities (WMHs) were automati- subjects. The difference in groups subdivision (4 versus 3)
callysegmentedontheFLAIRsequencesbyusingpreviously was mandatory to obtain group with volumetric statistical
describedalgorithms[32,35].Briefly,theprocedureincludes significantdifference.
(i) filtering of FLAIR images to exclude radiofrequency At first, we choose to focus on the changes of brain
inhomogeneities,(ii)segmentationofbraintissuefromcere- rhythmicityinducedfromhippocampalatrophyalone.Sub-
brospinal fluid, (iii) modelling of brain intensity histogram jectsweresubdividedinfourgroupsbasedonhippocampal
asaGaussiandistribution,and(iv)classificationofthevoxels volume of a normal control sample matched for age, sex,
whoseintensitieswere≥3.5SDsabovethemeanasWMHs andeducationascomparedtothewholeMCIgroup.Inthe
[32,35],TotalWMHsvolumewascomputedbycountingthe normal group the female/male ratio was 93/46, mean age
number of voxels segmented as WMHs and multiplying by was 68.9 (SD±10.3), mean education was years 8.9 (SD±
thevoxelsize(5mm3).Tocorrectforindividualdifferences 9.4). The mean and standard deviation of thehippocampal
in head size, hippocampal, amygdalar and WMHs volumes volume in the normal old population of 139 subjects were
were normalized to the total intracranial volume (TIV), 5.72±1.1cm3 .Inthisway,4groupswereobtained:theno
obtained by manually tracing with DISPLAY the entire atrophy group with hippocampal volume equal or superior
intracranial cavity on 7mm thick coronal slices of the T1 to the normal mean (total hippocampal volume from
weighted images. Both manual and automated methods 6.79cm3 to5.75cm3 ;G1);themildatrophygroupwhich
used here have advantages and disadvantages. Manual seg- has hippocampal volume within 1.5SD below the mean
mentation of the hippocampus and amygdala is currently of hippocampal normal control value (total hippocampal
consideredthegoldstandardtechniqueforthemeasurement volume from 5.70 to 4.70cm3; G2); the moderate atrophy
of such complex structures. The main disadvantages of groupwhichhashippocampalvolumebetween1.5and3SD
manual tracing are that it is operator dependent and time belowthemeanofnormalhippocampus(totalhippocampal
consuming. Conversely, automated techniques are more volume from 4.65 to 3.5cm3; G3); the severe atrophy
reliable and less time-consuming but may be less accurate groupwhichhashippocampalvolumebetween3and4.5SD
when dealing with structures without clearly identifiable below the mean of hippocampal normal control volume
borders. This, however, is not the case for WMHs, which (total hippocampal volume from 3.4 to 2.53cm3; G4). The
appearashyperintenseonFLAIRsequences. rationalefortheselectionof1,5SDwastoobtainreasonably
Leftandrighthippocampalaswellasamygdalarvolumes pathological groups based on hippocampal volume. A SD
wereestimatedandsummedtoobtainatotalvolume(indi- below 1.5 could recollect still normal population based on
vidual) of both anatomical structures. In turn, total amyg- hippocampalvolume.Ontheotherside,aSDover1.5could
dalarandhippocampalvolumesweresummedobtainingthe notallowanadequatesizeofallsubgroupsinstudy.
wholeAHCvolume.AHC(whole)volumehasbeendivided Subsequently,ANOVAwasperformedinordertoverify
intertilesobtainingthreegroups.Ineachgrouphippocam- (1) the difference of AHC volume among groups; (2) the
pal and amygdalar volumes (within AHC) have been com- difference of hippocampal and amygdalar volume within
puted. The last volumes were compared with the previous AHCamonggroups;(3)thedifferenceofhippocampaland
obtainedindividual(hippocampalandamygdalar)volumes. amygdalar volume individually considered among groups;
(4)NPSimpairmentbasedonACHatrophy.
Moreover, as a control analysis, in order to detect if
3.3. Statistical Analysis and Data Management. The anal- differenceinEEGmarkerswaslinkedtosignificantdifference
ysis of variance (ANOVA) has been applied as statistical in volume measurements, the volume of hippocampus
tool. At first, any significant differences among groups within AHC was compared with the hippocampal volume
in demographic variables, that is, age, education, MMSE individually considered, and the amygdalar volume within
score, and morphostructural characteristics, that is, AHC, AHCwascomparedwiththeamygdalarvolumeindividually
hippocampal, amygdalar, and white matter hyperintensities considered. This control analysis was performed through a
(WMHs) volume, were evaluated (Table1). Greenhouse- pairedt-test.
GeissercorrectionandMauchly’ssphericitytestwereapplied Subsequently,ANOVAwasperformedinordertocheck
to all ANOVAs. In order to avoid a confounding effect, differencesintheta/gammaandalpha3/alpha2relativepower
ANOVAs were carried out using age, education, MMSE ratio in the three groups ordered by decreasing tertile
score, and WMHs as covariates. For all statistical tests the values of the whole AHC volume. In each ANOVA, group
significancelevelwassetatP <0.05.Duncan’stestwasused was the independent variable, the frequency ratios was the
forposthoccomparisons.Inafirststudy[32]weconsidered dependent variable, and age, education, MMSE score, and
only the hippocampal volume and obtained 4 subgroups WMHs were used as covariates. Duncan’s test was used for
basedonthehippocampalvolumeatrophy.Inasubsequent post-hoccomparisons.Forallstatisticalteststhesignificance
study [33], given the importance of the amigdala in both levelwassetatP<0.05.
degenerative pathology and brain rhythm generation, we In order to check closer association with EEG markers,
considered the amygdalo-hippocampal volume as a whole, hippocampal volume and amygdalar volume within AHC
in order to investigate the entire AHC and to focus on the wereanalyzedseparately.Acontrolanalysiswascarriedout
hippocampal volume within theAHC itself. In this casewe alsoontheindividualhippocampalandamygdalarvolumes
obtain three groups based on AHC atrophy. Both the first basedondecreasingtertilevaluesforhomogeneitywiththe
and the second studies were performed on the same 79 mainanalysis.
InternationalJournalofAlzheimer’sDisease 7
Plot of means thefirstgroup(P <0.03).Theamygdalarvolumedifference
2-way interaction in the other groups (resp. P = 0.2 and 0.1) as well as
F(12.336)=2.87;P<0.0009 the difference in the volume of AHC-hippocampus versus
Full scalp
individualhippocampus(P =0.4inthefirst,P =0.5inthe
Equal size groups
5 second,andP = 0.1inthethirdgroup)wasnotstatistically
4.5 significant.
Tables 3 and 4 show the results of theta/gamma and
4
alpha3/alpha2 ratio in the groups based on the decrease of
3.5
whole AHC volume as well as, within the same group, the
wer 3 decreaseofhippocampalandamygdalarvolumesseparately
o
d p 2.5 considered.ANOVAshowsresultstowardssignificancewhen
n
Ba 2 amygdaloippocampalvolumeisconsideredgloballyinboth
theta/gamma (F = 2.77;P < 0.06) and alpha3/alpha2
1.5 2,76
ratio (F = 2.71;P < 0.07). When amygdalar and
2,76
1
hippocampal volumes were considered separately, ANOVA
0.5 resultsrevealedsignificantmaineffectofGroup,respectively,
Delta Theta Alpha 1 Alpha 2 Alpha 3 in theta/gamma ratio analysis (F = 3.46;P < 0.03)
2,76
Rhythms
for amygdalar and alpha3/alpha2 ratio for hippocampal
Group 1 Group 3 (F = 3.38;P < 0.03) decreasing volume. The ANOVA
2,76
Group 2 Group 4 did notshowsignificantresultsintheta/gammaratio when
Figure2:StatisticalANOVAinteractionamonggroupfactorsand considering hippocampal volume (F = 0.3;P < 0.7)
2,76
relativebandpowers(delta,theta,alpha1,alpha2,andalpha3),on and in alpha3/alpha2 ratio when considering amygdalar
thefullscalpregion.Thegroupsarebasedonmeanandstandard volume (F = 1.46;P < 0.2). The control analysis
2,76
deviations in a normal elderly sample. Group 1: no hippocampal
(individual volumes) did not show any significant result
atrophy; group 2: mild hippocampal atrophy; group 3: moderate neitherforhippocampal(theta/gamma,F =0.3;P <0.7;
hippocampal atrophy; group 4: severe hippocampal atrophy. Post 2,76
alpha3/alpha2, F = 2.15;P < 0.1) nor for amygdalar
hocresultsareindicatedinthediagram(see[32,35]). 2,76
volume(theta/gamma,F = 0.76;P < 0.4;alpha3/alpha2,
2,76
F =2.15;P<0.1).
2,76
3.4. Amigdalohyppocampal Atrophy MCI. Figure2 displays
the results for ANOVA analysis performed on 4 groups of
MCIconsideringgrowingvaluesofhippocampalatrphy.The 4.Discussion
results show a significant interaction between group and
bandpower(F(12,336) = 2,36);P < 0.007).Duncan’spost MCIandEEGMarkers:DegenerativeversusVascularImpair-
hoctestingshowedthatG3grouphasthehighestalpha2and ment. Alargebodyofliteraturehaspreviouslydemonstrated
alpha3powerstatisticallysignificantwithrespecttoallother that in subjects with cognitive decline an increase of theta
groups (P < 0.05;P < 0.006, resp.). The same trend was relative power [32, 33, 35], a decrease of gamma relative
presentinthesubsidiaryANOVA.Theseresultsshowthatthe power [32, 33, 35, 55], and an increase of high alpha as
relationshipbetweenhippocampalatrophyandEEGrelative compared to low alpha band are present [33]. On the
power is not proportional to the hippocampal atrophy and whole theta/gamma ratio and alpha3/alpha2 ratio could be
highlight that the group with a moderate hippocampal consideredreliableEEGmarkersofcognitivedecline.
volumehadaparticularpatternofEEGactivityascompared The amygdalohippocampal network is a key structure
toallothergroups. in the generation of theta rhythm. More specifically, theta
Table3summarizestheANOVAresultsofdemographic synchronization is increased between LA and CA1 regions
variables, that is, age, education, MMSE score, and mor- of hippocampus during long-term memory retrieval, but
phostructural characteristics, that is, hippocampal, amyg- not during short-term or remote memory retrieval [56,
dalar,andwhitematterhyperintensitiesvolumeinthewhole 57]. Theta synchronization in AHC appears to be apt to
MCI cohort as well as in the three subgroups in study. improvetheneuralcommunicationduringmemoryretrieval
Hippocampalandaymgdalarvolumesareconsideredasparts [57]. On the other hand, the retrieval of hippocampus-
of the whole AHC volume and are individually considered. dipendent memory is provided by the integrity of CA3-
Significantstatisticalresultswerefoundinhippocampaland CA1interplaycoordinatedbygammaoscillations[58].Our
amygdalar volume both within the AHC (resp., F = resultsconfirmandextendallpreviousfindings.Theatrophy
2,76
92.74;P < 0.00001andF = 33.82;P < 0.00001) and of AHC determines increasing memory deficits. The brain
2,76
were individually considered (resp., F = 157.27;P < oscillatory activity of this MCI state is characterized by an
2,76
0.00001andF = 132.5;P < 0.00001). The global AHC increase of theta/gamma ratio and alpha3/alpha2 relative
2,76
volume also showed significant results (F = 159.27;P < power ratio, confirming the overall reliability of these EEG
2,76
0.00001). Duncan’s post hoc test showed a significant markers in cognitive decline. Our results suggest that theta
increase (P < 0.01) in all comparisons. The paired t-test synchronizationismainlyduetotheamygdalaactivationor
showed significant difference between the volume of ACH- asasubsequentfinalneteffectwithintheAHCfunctioning
amygdalaandamygdalarvolumeindividuallyconsideredin driven by the amygdala excitation. The increase in theta
8 InternationalJournalofAlzheimer’sDisease
Table4:Relativepowerbandratiosinamygdalo-hippocampalcomplex(AHC),hippocampalandamygdalaratrophy.Hippocampaland
amygdalarvolumesrefertothewholeamygdalo-hippocampalcomplex(AHC)andaresingularlyconsidered(individual).
Hippocampal+amygdalarvolume theta/gammaratio(μv2) Pvalue alpha3/alpha2ratio(μv2) Pvalue
Group1 1.40±0.35 1.05±0.11
Group2 1.43±0.35 0.06 1.11±0.14 0.07
Group3 1.47±0.44 1.12±0.16
AHC-hippocampalvolume
Group1 1.39±0.27 1.04±0.11
Group2 1.48±0.45 0.7 1.11±0.15 0.03
Group3 1.43±0.41 1.12±0.14
AHC-amygdalarvolume
Group1 1.36±0.37 1.04±0.13
Group2 1.44±0.36 0.03 1.12±0.16 0.2
Group3 1.49±0.39 1.09±0.11
Individualhippocampalvolume
Group1 1.39±0.27 1.04±0.11
Group2 1.48±0.45 0.7 1.07±0.15 0.1
Group3 1.43±0.40 1.10±0.14
Individualamygdalarvolume
Group1 1.39±0.37 1.04±0.13
Group2 1.43±0.36 0.1 1.12±0.16 0.4
Group3 1.46±0.39 1.09±0.11
activitiesinAHC,representinganincreaseinneuronalcom- resultswereconfirmedbyacorrelationanalysisthatshowed
municationapttopromoteorstabilizesynapticplasticityin asignificantnegativecorrelationbetweenCVdamagescore
relation to the effort to retention of associative memories andalpha1andalpha2bandpowers.Inourresults,theCV
[59], could be active also during an ongoing degenerative damage did not show any impact on the alpha3 (or high
process.Theexcitationmechanismcouldbefacilitatedbythe alpha)power.Thisisaconfirmationofwhatwefoundinthe
lossofGABAinhibitoryprocess,determiningthedecreaseof previous study, where no differences between VaD patients
gammarhythmgeneration[58,60]. and normal elderly (but not in AD versus normal elderly)
As regards the CV damage, our results showed that subjectsweredetectedinthealpha3power.
the CV damage affected both delta and low alpha band Together,theseresultscouldsuggestdifferentgenerators
power (alpha1 and alpha2). In the delta band we observed forlowalphaandhighalphafrequencybands.Inparticular,
a power increase proportional to the CV damage, with a the low alpha band power could affect corticosubcortical
significant increase in the group with severe CV damage, mechanisms, such as corticothalamic, corticostriatal, and
as compared to the no-CV-damage group. The impact of corticobasal ones. This could explain the sensitivity of the
the CV damage on the delta power was confirmed by the low alpha frequency band to subcortical vascular damage.
significant positive correlation between CV damage score On the contrary, the alpha3 band power could affect to
anddeltapoweritself. a greater extent those corticocortical interactions based on
Theincreaseinthedeltabandpowercouldbeexplained synaptic efficiency prone to degenerative rather than CV
as a progressive cortical disconnection due to the slowing damages [38, 62]. In order to find reliable indices of CV
oftheconductionalongcorticosubcorticalconnectingpath- damage, we checked the theta/alpha1 band power ratio.
ways. Previous studies have shown the reliability of this kind of
This result confirmed the increase in the delta band approach in quantitative EEG in demented patients [21].
power we had observed in CV patients, as compared to The importance of this ratio lies in the presence of such
normal elderly subjects [37]. It is to be noted that the frequency bands on the opposite side of the TF, that is,
increase in the delta band power reflects a global state of the EEG frequency index most significantly affected by the
cortical deafferentation, due to various anatomofunctional CV damage. So, the theta/alpha1 band power ratio could
substrates,suchasstagesofsleep,metabolicencephalopathy, representthemostsensitiveEEGmarkerofCVdamage.The
orcorticothalamocorticaldysrhythmia[61].Inthelowalpha resultsshowedasignificantincreaseofthetheta/alpha1band
bandpower,weobservedasignificantdecreaseinthealpha power ratio in moderate and severe CV damage groups, as
2 band power for the groups with moderate and severe compared to mild and no-CV-damage groups. This ratio
CV damage, as compared to the no-CV-damage group. In increaseestablishesaproportionalincreaseofthethetaband
the alpah1 frequency band, there was a similar decrease power relative to the alpha 1 band power with respect to
althoughitdidnotreachstatisticallysignificantvalues.These the CV damage, even though a significant increase in the
InternationalJournalofAlzheimer’sDisease 9
theta band power per se (or a decrease in the alpha 1 band due to subcortical vascular damage (subcortical vascular
power per se) is not present. This could suggest a reliable MCI(svMCI))hasrecentlybeendescribed[74,75].Insuch
specificityforthetheta/alpha1bandpowerratioinfocusing study,MCIpatientswithCVetiologydevelopedadistinctive
thepresenceofasubcorticalCVdamage. clinical phenotype characterized by poor performance on
frontal tests and neurological features of parkinsonism
MCI, Cognitive Deficits (Memory and Attention), and EEG without tremor (impairment of balance and gait). These
Activity. The vulnerability and damage of the connections clinical features could be explained by our results. In CV
ofhippocampuswithamygdalacouldaffectreconsolidation patients,weobservedaslowingoftheafrequencyinthetwo
of long-term memory and give rise to memory deficits groupswithgreaterCVdamage,ascomparedtothegroups
and behavioural symptoms. Several experiments show that withlesserCVdamage.Thisisinlinewithapreviousstudy
amygdalaactivityisprominentduringtheperiodofintense [37]showingthemajoreffectoftheCVdamage,inpatients
arousal,forexample,theanticipationofanoxiousstimulus with vascular dementia (VaD) versus normal elderly and
[63] or the maintenance of vigilance to negative stimuli Alzheimer’s patients. A reasonable (although speculative)
[64]. So far, the theta synchronization induced by the explanation of the present results is that the CV-damage-
amygdala is deeply involved in endogenous attentional induced slowing of the a frequency start point could be
mechanism. Interestingly, the increase of high alpha syn- mainly attributed to the lowering of the conduction time
chronizationhasbeenfoundininternallycuedmechanisms of synaptic action potentials throughout corticosubcortical
of attention, associated with inhibitory top-down processes fibers,suchascorticobasalorcorticothalamicpathways[76].
[62]. Of note, the amygdala is intimately involved in Infact,experimentalmodelshavepreviouslyshownthatthe
the anatomophysiological anterior pathways of attention EEG frequency is due to axonal delay and synaptic time of
through its connections with anterior cingulated cortex, corticosubcortical interactions [77–79]. Most interestingly,
anteroventral, anteromedial, and pulvinar thalamic nuclei other studies have demonstrated that fiber myelination
[65]. The particular role of amygdala in negative human affects the speed propagation along cortical fibers and
emotionscouldindicatethatAHCatrophyisassociatedwith that this parameter is strictly correlated to the frequency
excessive level of subcortical inputs not adequately filtered range recorded on the scalp. In fact, a theoretical model
by attentive processing, determining fear and anxiety and consideringameanspeedpropagationinwhitematterfibers
generating cognitive interference in memory performance. of7.5m/s(togetherwithotherparameters)isassociatedwith
Of note, an altered emotional response is very frequent in a fundamental mode frequency of 9Hz [80], that is, the
MCIpatients[66,67].Inafeedbackprocess,thisalteration typical mode of scalp-recorded EEG. It is to be noted that
could determine a general state of “hyperattention” during acorrelationbetweenwhitematterdamageandwidespread
which top-down internal processes prevail on the bottom- slowing of EEG rhythmicity was found in other studies,
up phase, altering attention mechanism and preventing a following the presence of cognitive decline [81], multiple
correctprocessingofsensorystimuli.Focusedattentionhas sclerosis [82], or cerebral tumors [83]. The increase of the
been found impaired in MCI patients in particular when theta/alpha1 band power ratio in moderate and severe CV
they have to benefit from a cue stimulus [68–72]. This damage groups, as compared to mild and no-CV-damage
particular state could be useful for maintaining a relatively groups, could be the neurophysiological correlate of the
spared global cognitive performance, whereas it could fail functional slowing of the speed propagation of the electric
when a detailed analysis of a sensory stimulus is required. signalsinvascularimpairedsubjects.
This “hyperattentive” state could represent the attempt to
recollect memory and/or spatial traces from hippocampus ConflictofInterests
andtocombinethemwithinassociativeareasconnectedwith
hippocampusitself. Thecorrespondingauthordeclaresthereisnohaveanydirect
The increase of alpha3/alpha2 ratio in our results sup- financialrelationwiththecommercialidentitymentionedin
ports the concomitance of anterior attentive mechanism thepaperthatmightleadtoaconflictofinterestsforanyof
impairmentinsubjectswithMCI,eventhoughtherearenot theauthors.
overtclinicaldeficits.Themajorassociationoftheincreaseof
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