inclusion criteria provide heterogeneity

7172019 Inclusion Criteria Provide Heterogeneity

httpslidepdfcomreaderfullinclusion-criteria-provide-heterogeneity 19

Inclusion criteria provide heterogeneityin baseline pro 1047297 les of patients with mildcognitive impairment comparison of

two prospective cohort studies

Shoji Kawashima12 Kengo Ito1 Takashi Kato1 the SEAD-J Study Group

ABSTRACTBackground Mild cognitive impairment (MCI) isconsidered to represent a transitional stage betweenageing and Alzheimerrsquos disease (AD) To aim atidentifying neuroimaging measures associated withcognitive changes in healthy elderly and MCI patientslongitudinal multicentre studies are ongoing in severalcountries The patient profiles of each study are basedon unique inclusion criteria

Objectives The purpose of the study is to clarifydifferences in baseline profiles of MCI patientsbetween Studies on Diagnosis of Early AlzheimerrsquosDiseasedJapan (SEAD-J) and Alzheimerrsquos DiseaseNeuroimaging Initiative (ADNI) and to examine theassociation between baseline profiles and risk of earlyconversion to AD

Design Prospective cohort study

Setting and participants SEAD-J recruited 114patients from nine facilities in Japan A total of 200

patients in ADNI with fluorodeoxyglucosee

positronemission tomography (FDG-PET) were enrolled fromthe USA

Methods Baseline profiles were statistically analysedFor FDG-PET at a time of inclusion associationsbetween each profile and cerebral metabolic rate forglucose (CMRgl) were examined using SPM5 softwareIn each study the ratio of conversion to AD within the 1-year and 2-year period after inclusion was investigatedand differences in baseline profiles between ADconverters and non-converters were analysed

Results SEAD-J included MCI patients with moresevere verbal memory deficits and extracted patients

with higher depressive tendencies These differenceswere likely to be associated with criteria SEAD-Jexhibited a higher rate of conversion within 1 yearcompared with ADNI (245 vs 135) In FDG-PETanalyses of SEAD-J AD converters within 1 yearshowed more severe decrease of FDG uptake in bilateralinferior parietal regions compared with non-converters

Conclusions Different inclusion criteria provideddifferences in baseline profiles The severity of

memory deficit might cause increase of the ADconversion within 1 year Clinical outcomes ofmulticentre studies for early diagnosis of AD should be

interpreted carefully considering profiles of patients

INTRODUCTIONThe increasing prevalence of patients withdementia is a growing social problem Inparticular Alzheimerrsquos disease (AD) is acommon disease that causes progressivedementia Mild cognitive impairment (MCI) isconsidered to represent a transitional stagebetween ageing and AD1 and patients withMCI tend to progress to AD at a rate of

approximately 10e

15 per year

2 3

In thiscontext early diagnosis of patients who show

To cite Kawashima S Ito K

Kato T et al Inclusion

criteria provide heterogeneity

in baseline profiles of

patients with mild cognitive

impairment comparison of

two prospective cohortstudies BMJ Open 20122

e000773 doi101136

bmjopen-2011-000773

lt Prepublication history for

this paper is available online

To view these files please

visit the journal online (http

dxdoiorg101136

bmjopen-2011-000773)

Research group of the

Studies on Diagnosis of Early

Alzheimerrsquos DiseasedJapan

(SEAD-J) comprisedinvestigators from nine

different facilities The

investigators contributed to

the design and

implementation of SEAD-J

andor provided data but did

not participate in the

analyses of this report

Received 6 January 2012

Accepted 15 March 2012

This final article is available

for use under the terms of

the Creative CommonsAttribution Non-Commercial

20 Licence see

httpbmjopenbmjcom

For numbered affiliations see

end of article

Correspondence to

Dr Kengo Itokitoncgggojp

ARTICLE SUMMARY

Article focus- To aim at identifying neuroimaging measures

associated with cognitive changes in healthy

elderly and MCI patients longitudinal multicentrestudies are ongoing in several countries- The differences in baseline profiles of MCI

patients between Studies on Diagnosis of EarlyAlzheimerrsquos DiseasedJapan (SEAD-J) andAlzheimerrsquos Disease Neuroimaging Initiative(ADNI) multicentre studies are clarified

Key messages- In association with criteria SEAD-J recruited more

patients with pre-dementia AD who had severeverbal memory deficits compared with ADNI

- In SEAD-J AD converters within 1 year showedmore severe decrease of FDG uptake in bilateral

inferior parietal regions compared with non-converters SEAD-J exhibited a higher rate ofconversion within 1 year

- These results suggested that MCI patients withsevere memory loss at the time of inclusion hadan increased risk of early transition to AD

Strengths and limitations of this study- This study reinforces that the results of multi-

centre studies should be interpreted carefullyconsidering the impact of baseline profiles

- The present results were based on the analysis ofdata at the time of inclusion

Kawashima S Ito K Kato T et al BMJ Open 20122e000773 doi101136bmjopen-2011-000773 1

Open Access Research



an increased risk of future conversion to AD represents animportant step towards preventing progression of ADpathology when disease-modifying therapies for AD arefinally developed

Although the clinical evidence is not yet well estab-lished fluorodeoxyglucoseepositron emission tomog-raphy (FDG-PET) has recently been reported to provide

useful findings of the cerebral metabolic rate for glucose(CMRgl) in both patients with AD4 5 and MCI patients6

A pattern of CMRgl reduction in the posterior cingulatecortex and precuneus has been reported in MCIpatients7 and hypometabolism in these regions might contribute to prediction of clinical AD conversion8

Furthermore AD converters from among pre-MCIpatients have shown correlations between CMRgl andfuture memory decline9 Likewise FDG-PET appearspotentially useful for distinguishing MCI patients withincreased risk of progressive dementia from patients with lower risk of future AD conversion

Alzheimerrsquos Disease Neuroimaging Initiative (ADNI)

is a multicentre study aimed at identifying neuroimagingmeasures and biomarkers associated with cognitive andfunctional changes in healthy elderly MCI and ADsubjects10 ADNI was launched in 2003 by the NationalInstitute on Aging the National Institute of BiomedicalImaging and Bioengineering the Food and Drug Administration private pharmaceutical companies andnon-profit organisations as a $60 million 5-yearpubliceprivate partnership ADNI is the results of effortsby many co-investigators from a broad range of academicinstitutions and private corporations and subjects havebeen recruited from over 50 sites across the USA and

Canada (for additional information about ADNI seehttpwwwadni-infoorg) Studies on Diagnosis of Early Alzheimerrsquos Diseased Japan (SEAD-J) was launched in2005 by the National Center for Geriatrics and Geron-tology SEAD-J represents an ongoing follow-up of MCIpatients with the aim of achieving early prediction of ADconversion Both studies have been investigatingchanges of serial neuroimaging findings and neuro-psychological assessments based on different patient samples enrolled with unique inclusion criteria toextract patients at increased risk of AD Such differencesin criteria appear likely to affect AD conversion11

However the impact of difference in baseline profiles of MCI patients for AD conversion has not been studied yet The purpose of the study was to clarify thiscomparing the results of statistical and imaging analysesof different multicentre studies SEAD-J and ADNI Weinvestigated baseline profiles and AD conversion ratio within the 1-year and 2-year period after inclusion andthen statistically analysed differences in baseline profilesbetween AD converters and non-converters

MATERIALS AND METHODSSEAD-J participants

Data set of SEAD-J was obtained from nine facilities in Japan All data were checked and quality controlled at

National Center for Geriatrics and Gerontology A totalof 114 patients with MCI (mean age (6SD)708675 years 50 men 64 women) were enrolled A total of 56 normal age-matched subjects (20 men and 36 women) without evidence of neuropsychiatric impair-ment based on interviews were included to construct a normative imaging database All participants provided

informed consent in accordance with the trust ethicscommittee of National Center for Geriatrics andGerontology All data sets of clinical and FDG-PETfindings over a follow-up period of 2 years have acquired

Diagnosis of MCI was based on an interview withneurologists that contained evidence of reduced cogni-tive capacity normal activities of daily living and absenceof dementia12 All patients were free of significant underlying medical neurological or psychiatric illnessPatients were initially accessed using a neuro-psychological test battery including Mini-Mental StatusExamination (MMSE) Clinical Dementia Rating(CDR)13 Geriatric Depression Scale (GDS)14 15 and

Logical Memory subset of the Wechsler Memory ScaleRevised (WMS-R LM)16 In accordance with the inclu-sion criteria MCI patients were between 50 and 80 yearsold with an MMSE score $24 a GDS score 10 a WMS-R LM I score 13 an LM II parts A and part B score(maximum 50) 8 and a CDR memory box scorerestricted to 05 Patients with an educational leveldefined as the number of completed years of formaleducation lt6 years were excluded

ADNI participantsData used in the preparation of this article were

obtained from the ADNI Database (httpwwwloniuclaeduADNI) Data sets of clinical and baseline FDG-PET recruited from a total of 200 MCI patients (meanage 752671 years 134 men 66 women) were down-loaded from the ADNI public website (httpwwwloniuclaeduADNI) Data sets of baseline FDG-PET from102 normal subjects were used as reference data toperform group comparisons of FDG-PET between thesestudies MCI patients were without any other neuro-psychological disease or symptoms and between 55 and90 years old with an MMSE score $24 verbal memory deficit as measured by WMS-R LM II part A score(maximum 25) and a CDR memory box score 05 or 1

LM II part A score was used to select patients with verbalmemory deficit measured by education-adjusted scores825 (for $16 years of education nfrac14133) 425 (for8e15 years of education nfrac1466) or 225 (for 7 yearsof education nfrac141) In addition patients who hadexperienced major depression or bipolar disorder withinthe past year were excluded and patients witha Hamilton Depression Rating Scale17 score 12 (froma total of 17 items) were recruited

Neuropsychological test batteriesThe neuropsychological test batteries used in each study

had three differences regarding MMSE WMS-R LM IIand GDS scores In different subscores of MMSE

2 Kawashima S Ito K Kato T et al BMJ Open 20122e000773 doi101136bmjopen-2011-000773

Comparison of baseline profiles of MCI patients between SEAD-J and ADNI



patients in SEAD-J were scored using serial subtractionof 7 from 100 (5 points) while patients in ADNI werescored by reverse repetition of the word lsquoearthrsquo (5points) To adjust for this difference modified MMSEscore (maximum 25) was calculated without thesubscores from these 5-point subsets

WMS-R LM II score contains parts A and B and reflects

verbal memory deficits The total score is 50 points InSEAD-J the cut-off score of WMS-R LM II for inclusion was 850 In ADNI it was determined using the algo-rithm described above For comparison of both profilesonly part A score (25 points) was used for analysis andthe normalised cut-off score for inclusion were calcu-lated using a following calculation that took into account each weighting for the educational level + (cut-off score3 patient number of each category)total patient number Using this measurement the normalised cut-off score for ADNI was estimated as 66525 while that forSEAD-J was 425 The difference also indicated that SEAD-J used more severe criteria to include patients with

memory deficitsTo evaluate depressive tendencies ADNI used the

Hamilton Depression Rating Scale and GDS whileSEAD-J used a 15-item questionnaire (GDS-15) A higherGDS score ($11) reflects depressive tendencies andrepresents a reliable instrument to diagnose depressivedisorder1 4 1 5 GDS-15 was considered a suitable short-form test for an elderly population18 A higher GDS-15score ($6) was evaluated as having gt90 sensitivity andspecificity for depression in elderly individuals19

FDG-PET and analysesIn SEAD-J FDG-PET data at the time of inclusion wereconsolidated onto local servers Scans were performed ina resting state in a dark room 40e60 min after venousinjection of FDG Scans of MCI patients were compared with a normative reference database controlling forglobal activity using iSSP software (httpMediPhysicscom) and then Z scores of FDG uptake were calculated voxel by voxel

Three-dimensional stereotactic surface projections20

of Z scores were generated to visualise imaging differ-ences for MCI patients compared with age-matchedcontrols and AD converters compared with age-matchedcontrols In line with the same procedure mentioned

above we performed a comparison for scans of MCIpatients in ADNI using data sets restricted to partici-pants lt80 years old to reduce differences in age forcomparisons of results

We also performed correlation analyses to investigatethe impact of baseline patient profiles on CMRglreduction using SPM5 software (httpwwwfilionuclacukspm) Each image was deformed to the MontrealNeurological Imaging template and then normalised for variations in whole-brain measurements using propor-tionate scaling Post-processed images were smoothed toa spatial resolution of 8 mm full width at half maximum

Analyses were conducted using MMSE score WMS-R LMII score GDS score and age as independent variables

and CMRgl as the dependent variable Statistical para-metric maps for each of the contrasts and correlations were used in computations The level of significance wasset at plt001 (uncorrected)

Statistical analysesSPSS V170 was used for the analyses of baseline profiles

Independent sample t-tests were used to assess differ-ences in clinical and cognitive variables The c2 test was

used for the analysis of gender difference betweenstudies and used to determine group differences in theratio of AD conversion (AD converters vs non-convertersMCI stables) within the 1-year and 2-year period afterinclusion

RESULTSDifferences in criteria and clinical profilesThe inclusion criteria of SEAD-J and ADNI and thedifferences in demographic characteristics of MCIpatients are summarised in tables 1 and 2 In compari-sons of neuropsychological test batteries at the time of inclusion mean MMSE score was lower for SEAD-Jpatients (264619) than for ADNI patients (272617plt0001) and mean WMS-R LM score was lower forSEAD-J patients (18618) than for ADNI patients(40627 plt0001) However modified MMSE score didnot differ significantly between studies suggesting that there is little difference in global cognitive functioncompared with verbal memory deficits

MCI patients in SEAD-J showed a lower educationallevel (SEAD-J 115630 years ADNI 158629 yearsplt0001) The percentage of patients with education

level $16 years (corresponding to post-university) was184 in SEAD-J and 665 in ADNI indicating theinclusion of a larger proportion of patients with highereducation in ADNI A positive correlation between WMS-R LM score and education level was found in ADNIpatients (rfrac14030 plt0001) but not in SEAD-J patients

Table 1 Differences in inclusion criteria for mild cognitive

impairment

SEAD-J ADNI

Age (yrs) 50e

80 55e

90MMSE 24e30 24e30

CDR memory 05 05 or 1

WMS-R LM I 0e13 None

WMS-R LM II 0e8

GDS 0e10 None

HAM-D None 0e12

See the Materials and methods sectionADNI Alzheimerrsquos Disease Neuroimaging Initiative CDR memorymemory subscore for Clinical Dementia Rating GDS GeriatricDepression Scale HAM-D Hamilton Depression Rating ScaleMMSE Mini-Mental Status Examination SEAD-J Studies onDiagnosis of Early Alzheimerrsquos DiseasedJapan WMS-R LM IILogical Memory part II subset of the Wechsler Memory ScaleRevised WMS-R LM I Logical Memory part I subset of the

Wechsler Memory Scale Revised





(rfrac14004 pfrac14067) No association with MMSE scores wasfound in either study

Regarding depressive tendencies using GDS meanscore was higher in SEAD-J patients (43622) than in ADNI patients (16614 plt0001) In SEAD-J 18patients (9) were over the cut-off for GDS-15 (615points) while in ADNI no patients were over the cut-off (1130 points) Thus SEAD-J included more patients with higher depressive tendency compared with ADNIThe difference in GDS score might have been caused by the exclusive criteria using the Hamilton Depression

Rating Scale The mean age of patients was younger inSEAD-J (708675 years) compared with ADNI(752671 years plt0001) presumably due to theinclusion criteria for age

Baseline FDG-PET group comparisons and correlationanalyses

Compared with normal controls MCI patients in SEAD-Jshowed considerably lower CMRgl in the regions pref-erentially affected by AD including the precuneusposterior cingulate and parietotemporal regions (AD-associated hypometabolism) (figure 1A ) In ADNI MCIpatients exhibited similar patterns of reduced CMRgl inthese regions The CMRgl reduction was also found inmedial temporal regions with left dominance (figure1B) In both studies MCI patients showed lower CMRglin bilateral frontal regions compared with normalsubjects Furthermore in SEAD-J FDG-PET analysisrevealed that the converters during 1 year after inclusionshowed AD-associated hypometabolism compared with

non-converters The difference in hypometabolism wasmore severe in the converters within 1 year compared with the converters within the following 1 year (figure 2)

In correlation analyses for FDG-PET the associationbetween patient profiles and glucose metabolism aredepicted in figures 3 and 4 In SEAD-J bilateral inferiorparietal regions correlated with MMSE score whereas ADNI showed no specific regions (figure 3A ) Bothstudies showed different patterns of correlation with WMS-R LM score In SEAD-J a correlation was found inthe left inferior parietal region while ADNI showed

Table 2 Demographic characteristics of patients at the

time of inclusion

SEAD-J ADNI p Value

Age (yrs) 708675 752671 lt0001

Gender (MF) 5064 13466 lt0001

Education (yrs) 115630 158629 lt0001

MMSE 264619 272617 lt0001

Modified MMSE 224617 225615 0642

WMS-R LM 18618 40627 lt0001

GDS 43622 16614 lt0001

Values are mean6SD The Modified MMSE represents the sum oftotal scores except for different subscores in both studies(maximum 25) WMS-R LM is taken as the score for the LogicalMemory II part A (maximum 25)ADNI Alzheimerrsquos Disease Neuroimaging Initiative GDS GeriatricDepression Scale MMSE Mini-Mental Status Examination SEAD-J Studies on Diagnosis of Early Alzheimerrsquos DiseasedJapanWMS-R LM Logical Memory subset of the Wechsler MemoryScale Revised

Figure 1 3D-SSP analyses of

baseline fluorodeoxyglucosee

positron emission tomography in



(SEAD-J) (A) and Alzheimerrsquos

Disease Neuroimaging Initiative

(ADNI) (B) These are the results

of group comparison between MCI

patients and normal controls (NC)

MCI patients showed a significant

decrease of the cerebral metabolic

rate for glucose (CMRgl) not only

in the regions preferentiallyaffected by Alzheimerrsquos disease

(including the inferior parietal

lobules and precuneus) but also in

the frontal lobules Colour bar

indicates the mean Z score of

CMRgl LAT lateral view SUP

superior view INF inferior view

ANT anterior view POST

posterior view MED medial view

GLB reference region in global

brain CLB reference region in

cerebellum





correlations in the precuneus and left medial temporalregion (figure 3B) Furthermore GDS score showed aninverse correlation in the frontal regions In SEAD-J

regions with significant correlations showed a greaterdistribution over the lateral and inferior frontal regions(figure 4A ) As for correlations with age both studies






These are the results of group

comparisons between Alzheimerrsquos

disease (AD) converters and non-

converters AD converters showa greater reduction in glucose

metabolism for AD-associated and

frontal regions This

hypometabolism was more

evident in the converters within

1 year after inclusion compared

with the converters from 1 year to

2 years after inclusion (A) AD

converters within 1 year after

inclusion and non-converters (B)

AD converters from 1 year to

2 years after inclusion and non-

converters

Figure 3 Statistical parametricmapping of the brain regions

correlated with baseline profiles in



(SEAD-J) and Alzheimerrsquos


(ADNI) The regions displayed in

red indicate significant regional

hypometabolism (plt005) (A)

Correlation between lower Mini-

Mental Status Examination

(MMSE) scores and glucose

metabolism (B) Correlation

between lower Logical Memorysubset of the Wechsler Memory

Scale Revised (WMS-R LM)

scores and glucose metabolism





showed an inverse correlation in bilateral medial frontalregions (figure 4B)

Differences between AD converters and non-convertersIn comparisons with AD conversion within 2 years werevealed the difference in profiles between convertersand non-converters (table 3) Patients who had droppedout or returned to normal were excluded from statistical

analysis In terms of patients to follow-up and patientsdropping out the studies did not show any significant differences in clinical profiles The conversion ratioduring 1 year was higher in SEAD-J than in ADNI (245

vs 135 c

2frac14

533 plt

005) Conversely conversion ratioover 2 years showed no difference between studies(SEAD-J 356 ADNI 333 c

2frac140097 pfrac14077)

Comparing the baseline profiles associated with

Figure 4 Statistical parametric

mapping of the brain regions







red indicate significant regionalhypometabolism (plt005) (A)

Inverse correlation between

Geriatric Depression Scale (GDS)


(B) Inverse correlation between

age and glucose metabolism

Table 3 Differences in baseline profiles between the converters to AD and non-converters

SEAD-J ADNI

Convnon-conv p Value Convnon-conv p Value

1-year conversion

MMSE 253613266619 0002 26861827217 NS

Modified MMSE 216613226618 0012 218617225615 NS

WMS-R LM 0761319618 0003 2562342627 0004

GDS 4362042624 0003 1361417614 NS

Age (yrs) 706669716667 NS 755661757673 NS

Education (yrs) 121631115630 NS 158628159629 NS

1e2-year conversion

MMSE 259618264619 0001 271616273616 NS

Modified MMSE 221615225620 NS 225615225614 NS

WMS-R LM 1661919619 NS 3862743627 NS

GDS 4962639621 NS 1661215614 NS

AGE (yrs) 709664715665 NS 737676759668 NS


Values are mean6SD 1-year conversion AD conversion within 1 year after inclusion 1e2-year conversion AD conversion from 1 year to2 years after inclusionAD Alzheimerrsquos disease ADNI Alzheimerrsquos Disease Neuroimaging Initiative Conv AD converters GDS Geriatric Depression Scale MMSEMini-Mental Status Examination non-conv AD non-converters NS no significance SEAD-J Studies on Diagnosis of Early Alzheimerrsquos

Diseased

Japan WMS-R LM Logical Memory subset of the Wechsler Memory Scale Revised





conversion during 1 year of follow-up SEAD-J convertersshowed significantly lower MMSE and WMS-R LM scoresthan non-converters (plt001) In ADNI WMS-R LMscore was lower in converters (plt001) but no differ-ence in MMSE score was evident Regarding the profilesassociated with conversion from 1 year to 2 years afterinclusion MMSE score was lower for SEAD-J converters

than for non-converters (plt

005) Among ADNIconverters no profiles showed significant differences

DISCUSSIONFrom analyses of baseline profiles SEAD-J includedpatients with more severe verbal memory deficits andextracted patients with higher depressive tendenciescompared with ADNI These differences in profiles of MCI patients were likely to be associated with operatingcriteria In FDG-PET both studies showed considerably lower CMRgl in the regions preferentially affected by ADand the frontal cortices The baseline profiles providedcharacteristic pattern of correlations between CMRgl on

baseline FDG-PET and scores of neuropsychologicaltests

Despite some studies have reported associationsbetween lower MMSE score of AD patients and higher Zscore in the regions preferentially affected by AD2 1 2 2

such associations in MCI patients have not beendemonstrated In this study MCI patients in SEAD-J hadassociation between hypometabolism in bilateral inferiorparietal regions and MMSE score The modified MMSEscore showed same pattern of correlation (data not shown) However we could not find any associationbetween MMSE score of patients in ADNI and CMRgl as

a result of previous report23

In WMS-R LM score SEAD- J showed a weak regional correlation in the part of right inferior parietal cortex while ADNI showed correlationsin the precuneus and right dominant medialetemporalcortices These results might reflect difference in diseaseseverity of the patient samples that is how close anindividual is to a clinical transition to AD

Concerning the hypometabolism in frontal cortices it might be an additional finding associated with theconversion from MCI to AD8 In patients with depressedmood disorders an FDG-PET study has shown a lowerCMRgl in bilateral frontal and temporal cortices inferiorparietal lobules and left cingulate cortex24 In AD

patients with depressive syndrome a greater decrease of CMRgl has been found in right suprafrontal lobules thanin non-depressive AD25 In our analyses CMRgl in theright dominant suprafrontal regions showed an inversecorrelation with GDS scores In particular the SEAD-J which included patients with higher depressive tenden-cies showed wider regions with correlation compared with ADNI Although the prevalence of patients withdepressive tendencies was not as high in SEAD-J theinclusion of patients with depressive tendencies might affect CMRgl In addition CMRgl in medial frontalregions showed an inverse correlation with age indi-

cating the ageing effect of glucose metabolism26

or

possibly containing a partial volume effect27 Theseresults reflected patient demographics of each study

In baseline profiles high educational level was anothercharacteristic of patients in ADNI The WMS-R LM scorefor ADNI patients correlated with educational level Thiscorrelation was likely to be associated with categoricalinclusion criteria for educational level High education

might mask expression of dementia symptoms Severalstudies have supported the hypothesis that highly educated subjects tend to cope better with the onset of dementia28e30 In FDG-PET studies higher educationhas been documented as a proxy for brain functionalreserve31 32 The impact of educational level might complicate the interpretation of subtle changes inneuropsychological test results for patients with higheducation A combination of neuropsychological testing with FDG-PET might thus help the accuracy for ADdiagnosis in such cases One study reported an associa-tion between higher education and lower CMRgl in thetemporoparietal cortex and precuneus in AD and MCI

converters33 However we did not find evidence that high education affected AD conversion in MCI patientsThe impact of education remains controversial andmight depend on the patient sample34

We revealed that SEAD-J patients exhibited a signifi-cantly higher rate of conversion within 1 year afterinclusion compared with ADNI Deficits in verbalmemory and psychomotor speedexecutive functionabilities might be associated with conversion to AD35

Actually in the present analyses comparisons of baselineprofiles between AD converters and non-convertersrevealed that SEAD-J converters had lower global

cognitive and verbal memory compared with ADNIconverters Furthermore in SEAD-J AD convertersduring 1 year after inclusion showed more severe CMRglreductions in bilateral inferior parietal regionscompared with converters during the following yearBased on these results the difference in AD conversionratio might be dependent on the severity of pre-dementia AD reflecting that MCI patients with severebaseline memory deficits rapidly converted to AD It suggested that inclusion and diagnostic criteria werelikely to be associated with the incidence of ADHowever there was no difference in conversion ratioseen within 2 years of follow-up period Concerning thediscrepancy due to follow-up period it is likely that thedifference in AD conversion ratio may not be limited by criteria only but be affected by another factor such asgenotype in MCI population The CMRgl reductions in AD-associated regions have been reported in cognitively normal people with the apolipoprotein E 34 allelea common AD susceptibility gene many years before theonset of symptoms of cognitive disturbance36 It suggeststhat FDG-PET findings may associate with pathogenesisof AD Although our observation was too short to makeclear the impact of criteria and baseline profiles on therisk of AD conversion it is likely that the incidence of AD

may not have greater difference in groups with greater





susceptibility symptoms if there are no operationalcriteria as for prevalence in genotype

In our analyses these comparisons of different multicenter studies have some limitations Quality control protocols for data acquisition caused different pattern of CMRgl in comparison of FDG-PET betweenSEAD-J and ADNI We carried out the analyses

comparing the baseline FDG-PET between two studiesHowever the result contaminated non-specific changesespecially in the frontal and parietal regions In thisreason we presented the difference in glucose metab-olism between MCI patients and normal subjects ineach study In addition the present results were basedon data sets at the time of inclusion To clarify furtherassociation between each patientrsquos profile and risk of AD conversion multimodal analyses of data are neededfor longer follow-up period

In conclusion our study revealed that the participantsof each study showed some differences in baselineprofiles because the two studies applied own original

inclusion criteria to MCI patients SEAD-J had morestrict criteria to include patients with severe verbalmemory deficits The characteristics of baseline profilesare closely related to AD conversion ratio within 1 yearafter inclusion Furthermore we compared nationaldifferences between multicentre studies to show that inclusion criteria were associated with pattern of regional glucose metabolism We suggest that severity of AD assessed by neuropsychological tests were a functionof the recruitment criteria To evaluate the value of neuroimaging measures in the early diagnosis of AD theresults of multicenter studies even though focusing on

amnestic MCI should be compared carefully consid-ering difference in characteristics of inclusion criteriaand profiles

Author affiliations1Department of Clinical and Experimental Neuroimaging Center for

Development of Advanced Medicine for Dementia National Center for

Geriatrics and Gerontology Obu Aichi Japan2Department of Neurology Nagoya City University Graduate School of Medical

Science Nagoya Japan

Acknowledgements The authors thank Ken Fujiwara and Yuki Okamoto fortheir technical assistance and data acquisition of SEAD-J

Contributors The investigators within ADNI contributed to the design and

implementation of ADNI andor provided data but did not participate in the

analysis or writing of this report We had completely followed the review for

ADNI Publications Policy ADNI DPC approved it as acceptable for submission

to a journal

Funding SEAD-J was supported by the Health Labour Sciences Research

Grant from the Ministry of Health Labour and Welfare of Japan

(H17-Tyojyu-023) and the Research Funding for Longevity Sciences from

National Center for Geriatrics and Gerontology Japan

Competing interests None

Ethics approval SEAD-J was approved by the medical ethics committee of the

Center for Development of Advanced Medicine for Dementia National Center

for Geriatrics and Gerontology

Provenance and peer review Not commissioned externally peer reviewed

Data sharing statement No additional data available

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13 Morris JC The Clinical Dementia Rating (CDR) current version andscoring rules Neurology 1993432412e14

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16 Sullivan K Estimates of interrater reliability for the Logical Memorysubtest of the Wechsler Memory Scale-Revised J Clin Exp Neuropsychol 199618707e12

17 Hamilton M A rating scale for depression J Neurol Neurosurg Psychiatry 19602356e62

18 de Craen AJ Heeren TJ Gussekloo J Accuracy of the 15-itemgeriatric depression scale (GDS-15) in a community sample of theoldest old Int J Geriatr Psychiatry 20031863e6

19 Fountoulakis KN Tsolaki M Iacovides A et al The validation of theshort form of the geriatric depression scale (GDS) in Greece Aging (Milano) 199911367e72

20 Minoshima S Frey KA Koeppe RA et al A diagnostic approach inAlzheimerrsquos disease using three-dimensional stereotactic surfaceprojections of fluorine-18-FDG PET J Nucl Med 1995361238e48

21 Hanyu H Sato T Hirao K et al The progression of cognitivedeterioration and regional cerebral blood flow patterns in Alzheimerrsquosdisease a longitudinal SPECT study J Neurol Sci 201029096e101

22 Chase TN Foster NL Fedio P et al Regional cortical dysfunction in

Alzheimerrsquos disease as determined by positron emission tomographyAnn Neurol 1984(15 Suppl)S170e4

23 Langbaum JB Chen K Lee W et al Categorical and correlationalanalyses of baseline fluorodeoxyglucose positron emissiontomography images from the Alzheimerrsquos Disease NeuroimagingInitiative (ADNI) Neuroimage 2009451107e16

24 Hosokawa T Momose T Kasai K Brain glucose metabolismdifference between bipolar and unipolar mood disorders in depressedand euthymic states Prog Neuropsychopharmacol Biol Psychiatry 200933243e50

25 Lee DY Choo IH Jhoo JH et al Frontal dysfunction underliesdepressive syndrome in Alzheimer disease a FDG-PET study Am J Geriatr Psychiatry 200614625e8

26 Aston JA Cunningham VJ Asselin MC et al Positron emissiontomography partial volume correction estimation and algorithms J Cereb Blood Flow Metab 2002221019e34

27 Kantarci K Senjem ML Lowe VJ et al Effects of age on the glucosemetabolic changes in mild cognitive impairment AJNR Am J Neuroradiol 2010311247e53





28 Wilson RS Li Y Aggarwal NT et al Education and the course ofcognitive decline in Alzheimer disease Neurology 2004631198e202

29 Bennett DA Wilson RS Schneider JA et al Education modifies therelation of AD pathology to level of cognitive function in older personsNeurology 2003601909e15

30 Roe CM Xiong C Miller JP et al Education and Alzheimer diseasewithout dementia support for the cognitive reserve hypothesisNeurology 200768223e8

31 Stern Y Alexander GE Prohovnik I et al Inverserelationship between education and parietotemporalperfusion deficit in Alzheimerrsquos disease Ann Neurol 199232371e5

32 Perneczky R Drzezga A Diehl-Schmid J et al Schooling mediatesbrain reserve in Alzheimerrsquos disease findings of fluoro-deoxy-

glucose-positron emission tomography J Neurol Neurosurg Psychiatry 2006771060e3

33 Garibotto V Borroni B Kalbe E et al Education and occupation asproxies for reserve in a MCI converters and AD FDG-PET evidenceNeurology 2008711342e9

34 Landau SM Harvey D Madison CM et al Comparing predictors ofconversion and decline in mild cognitive impairment Neurology 201075230e8

35 Tabert MH Manly JJ Liu X et al Neuropsychological prediction ofconversion to Alzheimer disease in patients with mild cognitiveimpairment Arch Gen Psychiatry 200663916e24

36 Reiman EM Chen K Alexander GE et al Correlations betweenapolipoprotein E 34 gene dose and brain-imaging measurements ofregional hypometabolism Proc Natl Acad Sci U S A20051028299e302

Kawashima S Ito K Kato T et al BMJ Open 20122e000773 doi10 1136bmjopen-2011-000773 9




an increased risk of future conversion to AD represents animportant step towards preventing progression of ADpathology when disease-modifying therapies for AD arefinally developed

Although the clinical evidence is not yet well estab-lished fluorodeoxyglucoseepositron emission tomog-raphy (FDG-PET) has recently been reported to provide

useful findings of the cerebral metabolic rate for glucose(CMRgl) in both patients with AD4 5 and MCI patients6

A pattern of CMRgl reduction in the posterior cingulatecortex and precuneus has been reported in MCIpatients7 and hypometabolism in these regions might contribute to prediction of clinical AD conversion8

Furthermore AD converters from among pre-MCIpatients have shown correlations between CMRgl andfuture memory decline9 Likewise FDG-PET appearspotentially useful for distinguishing MCI patients withincreased risk of progressive dementia from patients with lower risk of future AD conversion

Alzheimerrsquos Disease Neuroimaging Initiative (ADNI)

is a multicentre study aimed at identifying neuroimagingmeasures and biomarkers associated with cognitive andfunctional changes in healthy elderly MCI and ADsubjects10 ADNI was launched in 2003 by the NationalInstitute on Aging the National Institute of BiomedicalImaging and Bioengineering the Food and Drug Administration private pharmaceutical companies andnon-profit organisations as a $60 million 5-yearpubliceprivate partnership ADNI is the results of effortsby many co-investigators from a broad range of academicinstitutions and private corporations and subjects havebeen recruited from over 50 sites across the USA and

Canada (for additional information about ADNI seehttpwwwadni-infoorg) Studies on Diagnosis of Early Alzheimerrsquos Diseased Japan (SEAD-J) was launched in2005 by the National Center for Geriatrics and Geron-tology SEAD-J represents an ongoing follow-up of MCIpatients with the aim of achieving early prediction of ADconversion Both studies have been investigatingchanges of serial neuroimaging findings and neuro-psychological assessments based on different patient samples enrolled with unique inclusion criteria toextract patients at increased risk of AD Such differencesin criteria appear likely to affect AD conversion11

However the impact of difference in baseline profiles of MCI patients for AD conversion has not been studied yet The purpose of the study was to clarify thiscomparing the results of statistical and imaging analysesof different multicentre studies SEAD-J and ADNI Weinvestigated baseline profiles and AD conversion ratio within the 1-year and 2-year period after inclusion andthen statistically analysed differences in baseline profilesbetween AD converters and non-converters

MATERIALS AND METHODSSEAD-J participants

Data set of SEAD-J was obtained from nine facilities in Japan All data were checked and quality controlled at

National Center for Geriatrics and Gerontology A totalof 114 patients with MCI (mean age (6SD)708675 years 50 men 64 women) were enrolled A total of 56 normal age-matched subjects (20 men and 36 women) without evidence of neuropsychiatric impair-ment based on interviews were included to construct a normative imaging database All participants provided

informed consent in accordance with the trust ethicscommittee of National Center for Geriatrics andGerontology All data sets of clinical and FDG-PETfindings over a follow-up period of 2 years have acquired

Diagnosis of MCI was based on an interview withneurologists that contained evidence of reduced cogni-tive capacity normal activities of daily living and absenceof dementia12 All patients were free of significant underlying medical neurological or psychiatric illnessPatients were initially accessed using a neuro-psychological test battery including Mini-Mental StatusExamination (MMSE) Clinical Dementia Rating(CDR)13 Geriatric Depression Scale (GDS)14 15 and

Logical Memory subset of the Wechsler Memory ScaleRevised (WMS-R LM)16 In accordance with the inclu-sion criteria MCI patients were between 50 and 80 yearsold with an MMSE score $24 a GDS score 10 a WMS-R LM I score 13 an LM II parts A and part B score(maximum 50) 8 and a CDR memory box scorerestricted to 05 Patients with an educational leveldefined as the number of completed years of formaleducation lt6 years were excluded

ADNI participantsData used in the preparation of this article were

obtained from the ADNI Database (httpwwwloniuclaeduADNI) Data sets of clinical and baseline FDG-PET recruited from a total of 200 MCI patients (meanage 752671 years 134 men 66 women) were down-loaded from the ADNI public website (httpwwwloniuclaeduADNI) Data sets of baseline FDG-PET from102 normal subjects were used as reference data toperform group comparisons of FDG-PET between thesestudies MCI patients were without any other neuro-psychological disease or symptoms and between 55 and90 years old with an MMSE score $24 verbal memory deficit as measured by WMS-R LM II part A score(maximum 25) and a CDR memory box score 05 or 1

LM II part A score was used to select patients with verbalmemory deficit measured by education-adjusted scores825 (for $16 years of education nfrac14133) 425 (for8e15 years of education nfrac1466) or 225 (for 7 yearsof education nfrac141) In addition patients who hadexperienced major depression or bipolar disorder withinthe past year were excluded and patients witha Hamilton Depression Rating Scale17 score 12 (froma total of 17 items) were recruited

Neuropsychological test batteriesThe neuropsychological test batteries used in each study

had three differences regarding MMSE WMS-R LM IIand GDS scores In different subscores of MMSE
























impairment

SEAD-J ADNI

Age (yrs) 50e

80 55e

90MMSE 24e30 24e30



WMS-R LM II 0e8

GDS 0e10 None

HAM-D None 0e12















time of inclusion

SEAD-J ADNI p Value

Age (yrs) 708675 752671 lt0001

Gender (MF) 5064 13466 lt0001

Education (yrs) 115630 158629 lt0001

MMSE 264619 272617 lt0001

Modified MMSE 224617 225615 0642

WMS-R LM 18618 40627 lt0001

GDS 43622 16614 lt0001


























cerebellum



























converters
























vs 135 c

2frac14

533 plt


2frac140097 pfrac14077)

















SEAD-J ADNI


1-year conversion

MMSE 253613266619 0002 26861827217 NS

Modified MMSE 216613226618 0012 218617225615 NS

WMS-R LM 0761319618 0003 2562342627 0004

GDS 4362042624 0003 1361417614 NS

Age (yrs) 706669716667 NS 755661757673 NS


1e2-year conversion

MMSE 259618264619 0001 271616273616 NS


WMS-R LM 1661919619 NS 3862743627 NS

GDS 4962639621 NS 1661215614 NS

AGE (yrs) 709664715665 NS 737676759668 NS



Diseased


















or




























to a journal














































































impairment

SEAD-J ADNI

Age (yrs) 50e

80 55e

90MMSE 24e30 24e30



WMS-R LM II 0e8

GDS 0e10 None

HAM-D None 0e12















time of inclusion

SEAD-J ADNI p Value

Age (yrs) 708675 752671 lt0001

Gender (MF) 5064 13466 lt0001

Education (yrs) 115630 158629 lt0001

MMSE 264619 272617 lt0001

Modified MMSE 224617 225615 0642

WMS-R LM 18618 40627 lt0001

GDS 43622 16614 lt0001


























cerebellum



























converters
























vs 135 c

2frac14

533 plt


2frac140097 pfrac14077)

















SEAD-J ADNI


1-year conversion

MMSE 253613266619 0002 26861827217 NS

Modified MMSE 216613226618 0012 218617225615 NS

WMS-R LM 0761319618 0003 2562342627 0004

GDS 4362042624 0003 1361417614 NS

Age (yrs) 706669716667 NS 755661757673 NS


1e2-year conversion

MMSE 259618264619 0001 271616273616 NS


WMS-R LM 1661919619 NS 3862743627 NS

GDS 4962639621 NS 1661215614 NS

AGE (yrs) 709664715665 NS 737676759668 NS



Diseased


















or




























to a journal



































































time of inclusion

SEAD-J ADNI p Value

Age (yrs) 708675 752671 lt0001

Gender (MF) 5064 13466 lt0001

Education (yrs) 115630 158629 lt0001

MMSE 264619 272617 lt0001

Modified MMSE 224617 225615 0642

WMS-R LM 18618 40627 lt0001

GDS 43622 16614 lt0001


























cerebellum



























converters
























vs 135 c

2frac14

533 plt


2frac140097 pfrac14077)

















SEAD-J ADNI


1-year conversion

MMSE 253613266619 0002 26861827217 NS

Modified MMSE 216613226618 0012 218617225615 NS

WMS-R LM 0761319618 0003 2562342627 0004

GDS 4362042624 0003 1361417614 NS

Age (yrs) 706669716667 NS 755661757673 NS


1e2-year conversion

MMSE 259618264619 0001 271616273616 NS


WMS-R LM 1661919619 NS 3862743627 NS

GDS 4962639621 NS 1661215614 NS

AGE (yrs) 709664715665 NS 737676759668 NS



Diseased


















or




























to a journal

















































































converters
























vs 135 c

2frac14

533 plt


2frac140097 pfrac14077)

















SEAD-J ADNI


1-year conversion

MMSE 253613266619 0002 26861827217 NS

Modified MMSE 216613226618 0012 218617225615 NS

WMS-R LM 0761319618 0003 2562342627 0004

GDS 4362042624 0003 1361417614 NS

Age (yrs) 706669716667 NS 755661757673 NS


1e2-year conversion

MMSE 259618264619 0001 271616273616 NS


WMS-R LM 1661919619 NS 3862743627 NS

GDS 4962639621 NS 1661215614 NS

AGE (yrs) 709664715665 NS 737676759668 NS



Diseased


















or




























to a journal






























































vs 135 c

2frac14

533 plt


2frac140097 pfrac14077)

















SEAD-J ADNI


1-year conversion

MMSE 253613266619 0002 26861827217 NS

Modified MMSE 216613226618 0012 218617225615 NS

WMS-R LM 0761319618 0003 2562342627 0004

GDS 4362042624 0003 1361417614 NS

Age (yrs) 706669716667 NS 755661757673 NS


1e2-year conversion

MMSE 259618264619 0001 271616273616 NS


WMS-R LM 1661919619 NS 3862743627 NS

GDS 4962639621 NS 1661215614 NS

AGE (yrs) 709664715665 NS 737676759668 NS



Diseased


















or




























to a journal







































































or




























to a journal










































































to a journal

























































inclusion criteria provide heterogeneity

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