Hippocampal Atrophy is Associated withSubjective Memory Decline: The PATH

Through Life Study

Nicolas Cherbuin, Ph.D., Kerry Sargent-Cox, Ph.D., Simon Easteal, Ph.D.,Perminder Sachdev, M.D., Ph.D., F.R.A.N.Z.C.P., Kaarin J. Anstey, Ph.D.

Received AugusAustralian NatioUniversity (SE),spondence andAustralian Natio

Supplementajgponline.org).

� 2014 Amehttp://dx.d

Am J Geriatr Ps

Objectives: To investigate whether subjective memory decline (SMD) in cognitively

healthy individuals is associated with hippocampal atrophy. Methods: Multiple

regression analyses assessing the relationship between hippocampal atrophy over 4

years and SMD at baseline and follow-up in 305 cognitively healthy individuals aged

60e64 years free from dementia, mild cognitive impairment, and other neurological

disorders. Results: SMD at baseline was not a significant predictor of hippocampal

atrophy. However, SMD at follow-up was associated with greater hippocampal atro-

phy. Associations were reduced but remained significant after controlling for anxiety

and depression symptomatology. Conclusions: Hippocampal atrophy was associated

with incident/persisting SMD and this association was not, or only partly, explained

by anxiety and depression symptomatology. These results are consistent with a bio-

logical origin to subjective memory decline. SMD should be included in screening and

neuropsychological batteries. (Am J Geriatr Psychiatry 2014; -:-e-)

Key Words: Cognitive decline, longitudinal, APOE ε4, MRI

ubjective memory decline (SMD) in ageing is of

Sparticular interest because it may be a prodromalsign of pathological processes leading to dementia,and because its relative ease of assessment makes itwell suited as a broad screen for individuals at risk.1,2

Moreover, “concern about change in cognition”contributes to the diagnosis of mild cognitiveimpairment (MCI), therefore ensuring that SMD isreflective of known pathological processes is highlyrelevant to clinicians.

t 26, 2013; revised July 4, 2014; accepted July 21, 2014.nal University (NC, KS-C, KJA), Canberra, Australia;Canberra, Australia; and the School of Psychiatry, Unireprint requests to Nicolas Cherbuin, Ph.D., Centre fornal University, Canberra, ACT 0200, Australia. e-mail: nal digital content is available for this article in the HTM

rican Association for Geriatric Psychiatryoi.org/10.1016/j.jagp.2014.07.009

ychiatry -:-, - 2014

In epidemiological studies prevalence of SMD inindividuals in their seventies has been reported torange between 22%e60% and to be somewhat higherin women.3e5 SMD prevalence, however, is likely tobe influenced by the formulation of questionsassessing its presence. For example, in the English2007 Adult Psychiatry Morbidity Survey, whichincluded 7,461 participants aged 16 years and over,31.7% reported forgetfulness in the last month butonly 6.4% reported having forgotten something

From the Centre for Research on Ageing, Health and Wellbeing,the John Curtin School of Medical Research, Australian Nationalversity of New South Wales (PS), Sydney, Australia. Send corre-Research on Ageing, Health and Wellbeing, 62A Eggleston Rd.,icolas.cherbuin@anu.edu.auL and PDF versions of this article on the journal’s Web site (www.

1

Hippocampal Atrophy and Subjective Memory Decline

important in the last week.6 Although the prevalenceof forgetfulness did not vary between age groups, anassociation between cognition was only found inthose above 60 years of age and only in those whoreported forgetting something important in the lastweek. In those aged 16e60 years the only predictorsof forgetfulness were anxiety and depressive andsomatic symptoms. These findings may indicate thatthe etiology of SMD varies with age, with SMD beingmore attributable to depression or anxiety symp-tomatology in younger age groups and to neurode-generative processes in older individuals.

A link between presence of SMD in later life andneurodegenerative processes is supported by studiesdemonstrating associations between SMD and demen-tia, MCI, or related pathological processes. SMD hasbeen found to be associated with APOE ε4 genotype,7

with an almost twofold increased risk of incident de-mentia,3,8,9 a fourfold increased risk of incident MCI,10

and with prospective cognitive decline.11,12 Associa-tions between SMD and objective neuropsychologicalmeasures have been found to be weak,13 however, andSMD has low predictive value for dementia.14 In addi-tion, SMD is linked with anxiety and depressionsymptomatology, thus making it a less-specific clinicalmarker and its significance more difficult to inter-pret,15,16 although it should be noted that mood disor-ders are also risk factors forAlzheimer disease (AD).17 Itis therefore possible that the association of SMD withcognitive decline is concurrent to or causally interre-lated with its association with affective symptoms.

Of methodological importance, ‘SMD’ and ‘subjec-tive memory complaints (SMCs)’ are terms that havebeen used interchangeably. Although the two con-structs are likely to overlap, SMD should not beconfusedwith SMC.Where SMD is assessed by askingindividuals, generally in community-based studies,whether they have experienced a change in memoryperformance, SMCs are based on individuals seekingclinical advice and reporting concerns and thereforemay have different origins and clinical significance.For example, in a longitudinal investigation ofmemory-clinic patients, whereas 41% of those report-ing memory complaints presented with normalcognitive function at baseline, 37% were classified ashavingMCI and 22%as having dementia.18Moreover,after a 3-year follow-up 9% of those without objectiveimpairment converted to MCI, and 27% of those withMCI progressed to dementia. Such associations

2

appear to be substantially stronger than those found inrelation to SMD.14 For example, Luck and colleagues19

investigated incident MCI in 732 individuals living inthe community and free of impairment and found thatthose reporting SMD (“Do you have problems withyour memory?”) were at only a twofold increased riskof developing MCI over an 8-year follow-up. Sargent-Cox and colleagues found that those reporting thatSMD interfered with their day-to-day life were at athreefold increased risk of developing MCI over 4years.10 Differences between reports and self-initiatedcomplaints may therefore reflect important distinc-tions in the nature or the timing of underlying pro-cesses, although some overlap is likely. For example,in cross-sectional analyses Anstey and colleagues20

found that individuals with stable MCI, who weremore likely to report having memory problems whichinterferedwith daily life, were alsomore likely to haveconsulted a doctor about memory concerns.

Few studies have investigated the association be-tween SMD and brain structure. In a cross-sectionalstudy Bartley et al.15 investigated associations be-tween SMD (“Do you feel like your memory orthinking is becoming worse?”) and white matter dis-ease and found no association. In another study Lamaret al.21 found that increased leukoaraiosis load wasassociated with poorer learning in individuals withSMD (‘‘Have you or anyone close to you noticed anyproblems or change in your memory?’’). In a thirdstudyofmemory clinic patients (N¼ 31;mean age: 67.6years) responding yes to “Do you feel like your mem-ory is becomingworse?” Scheef et al.22 found that SMDwere associated with smaller right but not left hippo-campal volume and with hypometabolism in the rightprecuneus and hypermetabolism in the right hippo-campus, with no significant differences in the corre-sponding left structures, thus suggestive of a possiblelaterality effect. Moreover, they found that thosereporting difficulties with their memory experiencedgreater memory decline over an 8-month follow-up.

We are aware of only one study that investigatedprospectively whether SMD was associated withlongitudinal change in brain structure. In a sample of1,336 individuals with a mean age of 72 years and freeof dementia at baseline, Stewart et al.23 found thatreporting SMD at follow-up 4 years later (“Do youhave habitual forgetfulness during daily activities/difficulties remembering recent new information?”)was associated with prior hippocampal and gray

Am J Geriatr Psychiatry -:-, - 2014

FIGURE 1. Sample selection process.

Cherbuin et al.

matter atrophy and increase in white matter lesions.Reporting SMD at baseline was only marginallyassociated with change in brain structure suggestingthat SMD follows rather than precedes cerebralchanges. It is unclear, however, whether similar as-sociations are also present in younger individuals inwhom cerebral changes are likely to be less promi-nent. Moreover, in a previous cross-sectional study ofthe same sample associations between SMD and brainvolumes were already present at baseline.24 It istherefore unclear whether larger regional volumesearlier in life provide some “brain reserve”whichmayhave a protective effect against SMD’s occurrence orwhether baseline associations indicate that changes incerebral structure associated with SMD occur beforethe early 70s but are not detectable until the early 60s.

The aim of the present study is to investigate the as-sociation between SMD at baseline and follow-up andhippocampalvolumeandatrophyover4years ina largecohort of community-based individuals in their 60s andfree of dementia or MCI using manual tracings on highresolution MRI scans. Other aims are to assess whetherdepression and anxiety symptomatologymight explainany association detected between SMD and hippo-campal structure and to confirm whether, as found byStewart et al., associations between SMD and brainstructure are more suggestive of brain changes preced-ing the occurrence of SMD rather than the reverse.

METHODS

Study Sample

The sample for this study comprised the partici-pants from the MRI sub-study of the first two wavesof the larger PATH Through Life project, which hasbeen described elsewhere.25 Briefly, participants(60e64 years) who were residents of the cities ofCanberra and Queanbeyan, Australia, were recruitedrandomly through the electoral roll to participate in alongitudinal study of ageing. Enrollment to vote iscompulsory for Australian citizens. A total of 2,551participants were included at baseline (2001), repre-senting a 58.3% response rate. Of those, 2,076 agreedto be contacted regarding magnetic resonance imag-ing (MRI) assessment; 622 randomly selected partic-ipants were offered a scan, and 479 completed astructural MRI scan. Of those, 431 underwent an MRI

Am J Geriatr Psychiatry -:-, - 2014

scan at wave 2 (2005) and after excluding participantswith MRI images of poor quality (N ¼ 42), neuro-logical disorders (N ¼ 66; MCI ¼ 20, abnormalMRI ¼ 22, stroke ¼ 21, epilepsy ¼ 3), and incompletedata (N ¼ 18), 305 participants were available forconsideration in the present investigation (see Fig. 1).All participants were screened for cognitive impair-ment and dementia, those scoring below specifiedthresholds received a neuropsychological assessmentand consensus clinical diagnoses were given basedon established criteria (see Anstey et al.20,26 for adetailed description of the methodology used). Nocase of dementia was present at either wave 1 orwave 2 in the MRI sub-sample.

Standard Protocol Approvals, Registrations, andPatient Consents

The study was approved by the Australian Na-tional University Ethics Committee and all partici-pants provided written informed consent.

3

Hippocampal Atrophy and Subjective Memory Decline

Sociodemographic and Health Measures

Total years of education, stroke, and depression andanxiety symptomatology (Goldberg depression andanxiety scale27), diabetes, and physical health (SF-12)were assessed by self-report. Body mass index wascomputedwith the formulaweight (kg)/height�height(m2) based on self-report of weight and height. Systolicand diastolic blood pressures were computed overtwo measurements using an Omron M4 monitor(Hoofddorp, the Netherlands) after a rest of at least 5minutes. Participants were classified as hypertensive iftheir mean diastolic or systolic blood pressure measureswere higher than 90 and 140 mm Hg, respectively, or ifthey took antihypertensive medication.

APOE genotypes were determined using Taqmanassays on genomic DNA obtained from buccalswabs, as previously described.28 Because the num-ber of individuals in the sample with APOE ε4/ε4homozygous genotypes was small (N ¼ 3), they werecombined with those with the two possible ε4 het-erozygous genotypes (ε4/ε2 and ε4/ε3) to form the “ε4carrier” genotype class, thereby, in effect, assuming adominant effect of the ε4 allele.

Subjective Memory Decline

SMDwas assessed by self-report at wave 1 andwave2.Participantswere asked the question “Doyou feel youcan remember things as well as you used to?” andwerecategorized as experiencing SMD if they responded no.

MRI Scan Acquisition

All participants were imaged with a 1.5-Tesla PhilipsGyroscan ACS-NT scanner (Philips Medical Systems,Best, The Netherlands) for T1-weighted 3-D structuralMRI in coronal orientation using a fast-field echosequence: Wave 1 repetition time (TR) ¼ 28.05 msec;echo time (TE)¼ 2.64msec;flipangle¼ 30�;matrix size¼256 � 256; field of view (FOV) ¼ 260 � 260 mm; slicethickness¼ 2.0mmandmid-slice tomid-slice distance¼1.0 mm, yielding over-contiguous coronal slices;Wave 2 TR¼ 8.93msec, TE¼ 3.57msec, flip angle¼ 8�,matrix size ¼ 256 � 256, FOV ¼ 256 � 256 mm. Sliceswere contiguous with slice thickness of 1.5 mm.

Image Analysis

Hippocampal volumes were determined by manu-ally tracing the periphery of the region of interest

4

(ROI) on each slice of a T1-weighted scan in coronalorientation using Analyze 5.0 (Brain ImagingResource, Mayo Clinic, Rochester, MN). The outliningof the hippocampus always proceeded from anteriorto posterior and was traced according to the protocoloutlined by Watson and colleagues29 with a modifi-cation suggested by Brierly et al.30 Volume estima-tions were repeated on 10 randomly selected scansand intraclass correlations between raters exceeded0.95 for all structures.31,32 Intracranial volume (ICV)was computedwith Freesurfer 4.3 (http://surfer.nmr.mgh.harvard.edu) for wave 1 and wave 2 images.

Statistical Analysis

Descriptive analyses were conducted using c2 testsfor categorical data and t tests to compare groups oncontinuous variables. Hippocampal volumes werenormalized for ICV using the formula:

adjusted volume ¼ raw volume� b� ðICV �mean ICVÞwhere b is the slope of regression of an ROI volumeon ICV. Associations between SMD and hippocam-pal volumes and atrophy were investigated usinghierarchical multiple regression analyses while con-trolling for sex, age, APOE genotype in model I andfor sex, age, APOE genotype, depression and anxietysymptomatology, diabetes, and hypertension formodel II. Diabetes and hypertension were added ascovariate due to their associations with neurodegen-erative processes, particularly in the hippocam-pus.33,34 Hippocampal atrophy was assessed byusing wave 2 volume as dependent variable andcontrolling for wave 1 volume as covariate in theanalyses, while also controlling for elapsed time be-tween assessments. In addition, because the imageacquisitions were different between waves, the dif-ference in ICV between wave 1 and wave 2 was alsocontrolled for by entering it as a covariate in the an-alyses, an approach already applied elsewhere.35 In-teractions between SMD and sex and APOE genotypewere also tested. Alpha was set at 0.05.

RESULTS

Participants were on average 62.6 years (range:60e65; SD: 1.39) at wave 1 with a mean follow-up of4 years (range: 3.3e4.6; SD: 0.21). Of the 305 partici-pants included, 70 reported SMD at wave 1 (23%)

Am J Geriatr Psychiatry -:-, - 2014

TABLE 1. Participants’ Demographic and Health Characteristics

Demographic Variables No SMD (N [ 218) W1 SMD (N [ 70) W2 SMD (N [ 56) W1DW2 SMD (N [ 39)

Female, N (%) 110 (50.50) 18 (25.71)** 18 (32.14)y 9 (23.10)AA

Agea, years (SD) 62.68 (1.32) 62.13 (1.42)** 62.41 (1.51) 62.26 (1.43)Educationa, years (SD) 14.08 (2.65) 14.78 (2.53) 14.36 (2.95) 14.50 (2.89)APOE ε4, N (%) 67 (30.70) 16 (22.86) 11 (19.64) 8 (20.51)Depression, score (SD) 1.72 (1.84) 0.76 (1.01)** 0.86 (1.38)yy 0.56 (0.82)AA

Anxiety, score (SD) 2.39 (2.40) 1.26 (1.56)** 1.25 (1.89)yy 1.10 (1.35)AA

Diabetes, N (%) 20 (9.20) 4 (5.70) 4 (7.10) 2 (5.10)Hypertension, N (%) 135 (61.90) 48 (68.60) 33 (58.90) 23 (59.00)Physical Health SF-12 (SD) 49.64 (8.90) 52.14 (7.04) 50.88 (8.03) 51.70 (7.77)BMI, kg/m2 (SD) 26.70 (4.85) 26.30 (3.71) 26.27 (3.70) 25.95 (3.88)Systemic BP, mm Hg (SD) 139.64 (18.29) 141.71 (18.08) 140.58 (17.84) 140.09 (19.20)Diastolic BP, mm Hg (SD) 82.84 (10.48) 85.96 (11.41)* 86.05 (12.44) 86.47 (13.22)Left HC, mm3 (SD) 2,815.21 (436.53) 2,905.65 (406.13) 2,861.72 (347.23) 2,882.29 (361.67)Right HC, mm3 (SD) 2,880.06 (466.45) 2,930.99 (423.15) 2,934.08 (365.57) 2,930.68 (388.23)

Notes: SMD: subjective memory decline; SF-12: short form of the Health Survey; BMI: body mass index; BP: blood pressure; W1: wave 1;W2: wave 2.

Differences were tested with t tests (df: W1 ¼ 286, W2 ¼ 272, W1þW2 ¼ 255) for continuous variables and c2 tests (df ¼ 1) for categoricalvariables; difference between W1 SMD and no SMD significant at *p <0.05 and **p <0.01; difference between W2 SMD and no SMDsignificant at yp <0.05 and yyp <0.01; difference between W1þW2 SMD and no SMD significant at AAp <0.01.

aAt wave 1.

Cherbuin et al.

and 56 at wave 2 (18%), with 39 participants report-ing SMD both at wave 1 and 2 (13%) and 31 partic-ipants reporting SMD at wave 1 but not at wave 2(44%). Demographic measures for all participants arepresented in Table 1 for each SMD group. Those whoreported SMD at wave 1 were more likely to be male,were slightly younger, had lower depression andanxiety symptomatology, and had a higher diastolicblood pressure than those who did not. Those whoreported SMD at wave 2 or at both waves were morelikely to be male and had lower depression andanxiety symptomatology but did not differ in age ordiastolic blood pressure (see Table 1).

Because ICVs at wave 1 andwave 2 differed,with thewave 2 volume being slightly (2.7%) but significantlysmaller (t(332) ¼ 8.185, p <0.001), the possible impact ofICV differences was further investigated with correla-tional analyses (not shown) which demonstrated thatthe difference in ICV between wave 1 and 2 explainedless than 1.5% of the variance in ROI volume change.

Association between hippocampal volume or atro-phyandSMDpresentat eitherwave1,wave2,or atbothwaves1and2arepresented inTables 2, 3, and4. Inafirstmodel, analyseswere controlled for sex, age, andAPOEgenotype and in the second model depression andanxiety symptomatology, diabetes, and hypertensionwere controlled for in addition to confounders includedin the first model. Atrophy was assessed by controllingfor wave 1 volume and time between wave 1 and 2

Am J Geriatr Psychiatry -:-, - 2014

assessments while predicting wave 2 volume. Theseanalyses showed that SMD at wave 1 (Table 2) was notassociatedwith hippocampalvolumes atwave 1 orwithhippocampal atrophy over 4 years in either models. Incontrast, SMD at wave 2 (Table 3) was negatively asso-ciated with left (trend) and right hippocampal volumesat wave 2 as well as with left and right hippocampalatrophy. These associations were attenuated butremained significant, except for left hippocampal atro-phy (trend), after controlling for depression and anxietysymptomatology in model II. Moreover, presence ofSMDat bothwave 1 and 2 (Table 4)was associatedwithgreater right but not left hippocampal atrophy andwithlower right but not left wave 2 hippocampal volumes.No significant association was detected in relation towave 1 hippocampal volume (data not shown). Theseassociations remained significant for atrophy (trend forvolume) after controlling for depression and anxietysymptomatology in model II. None of the sex or APOEinteractions reached significance.

Additional analyses were conducted to investigateassociations between SMD and hippocampal vol-ume/atrophy in those who only reported SMD atwave 1 and in those who only reported SMD at wave2 (excluding those with SMD at both waves). Socio-demographic characteristics for these groups are re-ported in Supplementary Table A1 (available online),and associations with hippocampal volume/atrophyare presented in Tables A2 and A3 (available online).

5

TABLE

2.

AssociationsBetwee

nSM

Dat

Wav

e1an

dHippoca

mpal

Volumeat

Wav

e1an

dAtrophyBetwee

nWav

e1an

dWav

e2(N

[305

)

Models

III

Wav

e1Hippoca

mpal

Volumea

,bHippoca

mpal

Atrophya,c

Wav

e1Hippoca

mpal

Volumea

,bHippoca

mpal

Atrophya,c

Left

Right

Left

Right

Left

Right

Left

Right

b(SE)

pb(SE)

pb(SE)

pb(SE)

pb(SE)

pb(SE)

pb(SE)

pb(SE)

p

Sex

L279(48)

0.001

L327(50)

0.001

L99(37)

0.008

L177(38)

0.001

L278

(48)

0.001

L325(50)

0.001

L99(37)

0.008

�43(185

)0.81

7Age

�13(17)

0.45

1�1

7(18)

0.35

03(13)

0.81

27(13)

0.56

5�1

3(17)

0.45

717

(18)

0.33

52(12)

0.87

66(13)

0.62

2APOEε4

3(52)

0.96

6�1

2(55)

0.82

3L

98(38)

0.01

L89(38)

0.022

3(52)

0.95

7�1

1(54)

0.84

0L95(38)

0.012

L86(38)

0.025

Hyp

ertension

�27(49)

0.58

7�4

6(40)

0.24

9�2

1(36)

0.56

4�3

1(36)

0.39

1�2

5(49)

0.60

820

(51)

0.70

0�1

8(36)

0.61

4�2

8(36)

0.44

2Diabetes

60(84)

0.47

125

(88)

0.78

1170(61)

0.006

158(61)

0.010

�64(84)

0.45

318

(88)

0.83

5159

(61)

0.011

144(62)

0.020

Dep

ression

5(18)

0.77

828

(19)

0.13

816

(14)

0.21

419

(13)

0.15

7Anxiety

�10(14)

0.46

5�1

9(14)

0.17

44(10)

0.65

61(10)

0.92

7SM

Dat

W1

18(57)

0.76

0�4

6(60)

0.45

017

(42)

0.69

2�3

3(42)

0.43

912

(59)

0.83

8�4

0(61)

0.51

436

(43)

0.40

2�1

5(43)

0.73

0Part.Eta2

0.00

00.00

20.00

00.00

10.00

00.00

10.00

20.00

0

Notes:S

ignificant

resu

ltsat

p<0.05

arehigh

lighted

inthetablewithbo

ldfont.b

:unstand

ardized

coefficien

t;SE

:stand

arderror;W

1:wav

e1;

W2:

wav

e2.

a After

norm

alizationforintracranial

volume.

Multipleregression

analyses

(df¼

304)

controlling

forbsex,

age,

APO

Ege

notype

(mod

elI);a

ndc sex,a

ge,W

1eW2intracranial

volumedifferenc

e,APO

Ege

notype

,elaps

edtime

betw

eenassessmen

t,an

dba

selin

evo

lume(m

odel

II).Atrop

hyin

mod

elIIis

assessed

bycontrolling

forba

selin

ehipp

ocam

palv

olum

e,thereforeapo

sitive

associationreflects

less

atroph

y.

6

Hippocampal Atrophy and Subjective Memory Decline

DISCUSSION

The main finding of this study was that SMD atfollow-up, but not at baseline, was associated withlongitudinal hippocampal atrophy over 4 years. Thisis an important result because it is more consistent inour view with previous findings that SMD tends tofollow rather than precede cerebral changes. More-over, this effect was found in younger individuals(62e66 years) than those surveyed in a previousstudy23 (72e76 years). Interestingly, although Stew-art et al. found that baseline SMD at age 72 wasassociated with brain structure in cross-sectional an-alyses, associations between baseline SMD and brainchanges over the following 4 years were low. In thepresent investigation baseline SMD was not associ-ated with baseline hippocampal volume. This mayindicate that a link between SMD and cerebralchanges becomes detectable in the early 60s withoutprior association earlier in life. This explanation isconsistent with previous findings from the English2007 Adult Psychiatry Morbidity Survey whichshowed that forgetfulness is equally prevalent acrossthe adult lifespan but that an association betweenforgetfulness and cognition only becomes apparent inthose aged greater than 60 years.6 It is also consistentwith revised models of biomarker progression pro-posed by Jack et al., which suggest that those atincreased risk of developing AD present with rela-tively stable hippocampal volumes although some-what below the norm until the early 60s, after whicha progressive decline is observed.36

Combined with other findings in the literature thepresent results appear to indicate that detectablevolumetric differences associated with neurodegen-erative processes predictive of SMD become salient inthe early 60s and seem to mostly precede the emer-gence of functional difficulties. In the mid to late 60svolumetric changes and SMD seem to co-occur, asshown in our and Scheef et al.’s22 cross-sectional an-alyses at a similar age. In the late 60s and 70s SMDbecomes more strongly associated with the develop-ment of MCI and dementia,14,19 conditions whoseneurodegenerative impact are well documented. Itshould also be noted, however, that in the presentinvestigation a sub-sample of those with SMD atwave 1 who also reported SMD at wave 2 did presentwith prospective hippocampal atrophy, although this

Am J Geriatr Psychiatry -:-, - 2014

TABLE

3.

AssociationsBetwee

nSM

Dat

Wav

e2an

dHippoca

mpal

Volumeat

Wav

e2an

dAtrophyBetwee

nWav

e1an

d2(N

[305)

Models

III

Wav

e2Hippoca

mpal

Volumea

,bHippoca

mpal

Atrophya

,cWav

e2Hippoca

mpal

Volumea

,bHippoca

mpal

Atrophya

,c

Left

Right

Left

Right

Left

Right

Left

Right

b(SE)

pb(SE)

pb(SE)

pb(SE)

pb(SE)

pb(SE)

pb(SE)

pb(SE)

p

Sex

L228(39)

0.001

L296(39)

0.001

L110(36)

0.003

L183

(37)

0.001

L229(39)

0.001

L296(39)

0.001

L113(37)

0.002

L187

(37)

0.001

Age

�4(14)

0.77

23(14)

0.84

31(12)

0.94

07(12)

0.54

7�5

(15)

0.71

51(14)

0.94

01(12)

0.97

87(12)

0.58

4APOEε4

L106(43)

0.015

L95(43)

0.027

L106(38)

0.005

L96(38)

0.012

L104(43)

0.017

L92(43)

0.032

L103(38)

0.008

L91(38)

0.018

Hyp

ertension

�45(40)

0.26

8�4

6(40)

0.24

9�2

5(36)

0.48

6�3

9(36)

0.28

3�4

1(40)

0.31

6�4

9(50)

0.33

0�2

6(36)

0.46

5�4

1(36)

0.26

2Diabetes

194(69)

0.005

174(69)

0.020

167(81)

0.006

158

(61)

0.010

184(70)

0.006

158(70)

0.023

159(61)

0.010

150

(61)

0.015

Dep

ression

�16(15)

0.28

229(15)

0.049

�1(12)

0.11

0�3

(12)

0.79

7Anxiety

�3(11)

0.82

1�8

(11)

0.49

48(10)

0.44

310

(11)

0.32

0SM

Dat

W2

�97(50)

0.05

5L117(50)

0.020

L88(44)

0.046

L116

(44)

0.009

�87(51)

0.09

0L103(51)

0.044

�79(45)

0.08

0L

107

(46)

0.019

Part.Eta2

0.011

0.015

0.009

0.014

0.008

0.011

0.007

0.012

Notes:S

ignificant

resu

ltsat

p<0.05

arehigh

lighted

inthetablewithbo

ldfont.b

:unstand

ardized

coefficien

t;SE

:stand

arderror;W

1:wav

e1;

W2:

wav

e2.

a After

norm

alizationforintracranial

volume.

Multipleregression

analyses

(df¼

304)

controlling

forbsex,

age,

APO

Ege

notype

(mod

elI);a

ndc sex,a

ge,W

1eW2intracranial

volumedifferenc

e,APO

Ege

notype

,elaps

edtime

betw

eenassessmen

t,an

dba

selin

evo

lume(m

odel

II).Atrop

hyin

mod

elIIis

assessed

bycontrolling

forba

selin

ehipp

ocam

palv

olum

e,thereforeapo

sitive

associationreflects

less

atroph

y.

Am J Geriatr Psychiatry -:-, - 2014

Cherbuin et al.

effect was smaller than that detected in all those withSMD at wave 2. This appears to suggest that eitherSMD preceded brain changes in these individuals orthat the neurodegenerative processes were initiatedearlier in this group. Unfortunately, this study cannotprovide conclusive answers to these questions andfuture investigations including multiple assessmentswill be able to test these hypotheses with time-laganalyses.

Interestingly, a number of our analyses, particu-larly in those reporting SMD at both assessments,demonstrated associations with the right but not theleft hippocampus. These findings are consistent withcross-sectional results reported by Scheef et al.22

showing smaller right but not left hippocampal vol-umes in those reporting SMD. Such effects should befurther investigated in future studies because the leftand right hemispheres have been reported to differ intheir vulnerability to AD neurodegenerative pro-cesses, which tend to start earlier and progress fasterin the left hemisphere.37,38

The prevalence of SMD in the present sample wassimilar to rates reported in the literature for epidemio-logical sampleswith23%reportingSMDatbaselineand18% at follow-up.3,23 Because individuals with demen-tia, MCI, or neurological disorder were excluded, SMDwas not associated with pre-existing clinical disorders.This suggests that it might be a useful marker, ratherthan a co-morbid feature, of prior hippocampal atro-phy, which is itself a predictor of future cognitivedecline and dementia.

These findings elicit important questions. BecauseSMD has been shown to be associated prospectivelywith dementia and cognitive decline, it would beparticularly useful to know whether SMD in early oldage is the consequence of developing AD or vascularpathology, or of other causes. Significant associationsbetween SMD and increase in white matter lesionssupport a vascular origin. Increased prevalence ofSMD in APOE ε4 carriers,7 however, would suggest arole of amyloidosis. One postmortem study hasinvestigated associations between SMD (“How oftendo you have trouble remembering things”, “How isyourmemory compared to 10 years ago”) and neuriticplaques and neurofibrillary tangles and found thatthose reporting memory decline antemortem hadhigher AD pathology.39 Importantly, this associationwas found both in those diagnosed with AD andthose without, and although the main analyses were

7

TABLE

4.

AssociationsBetwee

nSM

DPresentat

Both

Wav

es1an

d2in

theSa

meIn

dividualsan

dHippoca

mpal

Volumeat

Wav

e2an

dAtrophyBetwee

nWav

e1an

d2

(n[

257)After

ControllingforAge

,Gen

der,an

dAPOEGen

otype(M

odel

I)an

dAfter

ControllingforAge

,Gen

der,APOEGen

otype,

Diabetes,Hypertension,

Dep

ressivean

dAnxiety

Symptomatology

(Model

II).

Models

III

Wav

e2Hippoca

mpal

Volumea

,bHippoca

mpal

Atrophya,c

Wav

e2Hippoca

mpal

Volumea

,bHippoca

mpal

Atrophya

,c

Left

Right

Left

Right

Left

Right

Left

Right

b(SE)

pb(SE)

pb(SE)

pb(SE)

pb(SE)

pb(SE)

pb(SE)

pb(SE)

p

Sex

L201

(40)

0.001

L293(42)

0.001

L91(38)

0.017

L178(40)

0.001

L200(41)

0.001

L290

(42)

0.001

L93(38)

0.016

L180

(40)

0.001

Age

13(15)

0.38

78(15)

0.61

718

(13)

0.17

515

(14)

0.26

9�8

(15)

0.58

2�4

(15)

0.79

2�1

8(13)

0.17

615

(14)

0.27

1APOEε4

L117

(44)

0.009

L100(45)

0.028

L119(39)

0.002

L113(40)

0.006

L98(45)

0.031

�82(45)

0.07

3L121(39)

0.002

L111

(41)

0.007

Hyp

ert

�64(41)

0.12

0�5

9(42)

0.16

4�5

8(36)

0.11

8�6

1(38)

0.11

0�4

1(40)

0.31

6�4

9(50)

0.33

0�5

8(37)

0.11

6�6

2(38)

0.10

4Diabetes

253

(71)

0.001

223(73)

0.003

220(63)

0.001

204(65)

0.002

184(70)

0.006

158

(70)

0.023

214(64)

0.001

200

(66)

0.003

Dep

ression

23(15)

0.13

741(16)

0.009

7(13)

0.60

42(13)

0.86

8Anxiety

�2(12)

0.84

6�1

1(12)

0.36

6�1

(11)

0.92

04(11)

0.75

0SM

Dat

W1þ

W2

�60(57)

0.29

4L131(58)

0.026

�52(50)

0.29

9L114(52)

0.029

�44(60)

0.46

3�1

03(60)

0.08

8�4

6(52)

0.37

5L

107

(54)

0.046

Part.Eta2

0.00

40.016

0.00

30.012

0.00

20.009

0.00

20.010

Notes:S

ignificant

resu

ltsat

p<0.05

arehigh

lighted

inthetablewithbo

ldfont.b

:unstand

ardized

coefficien

t;SE

:stand

arderror;W

1:wav

e1;

W2:

wav

e2.

a After

norm

alizationforintracranial

volume.

Multipleregression

analyses

(df¼

304)

controlling

forbsex,

age,

APO

Ege

notype

(mod

elI);a

ndc sex,a

ge,W

1eW2intracranial

volumedifferenc

e,APO

Ege

notype

,elaps

edtime

betw

eenassessmen

t,an

dba

selin

evo

lume(m

odel

II).Atrop

hyin

mod

elIIis

assessed

bycontrolling

forba

selin

ehipp

ocam

palv

olum

e,thereforeapo

sitive

associationreflects

less

atroph

y.

8

Hippocampal Atrophy and Subjective Memory Decline

conducted using a global measure of AD pathology(neuritic plaques and neurofibrillary tangles com-bined), further analyses showed that both patholog-ical features equally predicted the presence of SMD.Moreover, adjusting for depressive symptomatologyand chronic health conditions did not substantiallymoderate these associations. In aggregate, thesefindings suggest both a vascular and an AD compo-nent to SMD, but it is not clear whether this is alsolikely to be the case in early old age and this questionshould be further scrutinized in future research.Depression and anxiety are important confounders

that are known to be associated with SMD andmemory complaints across the lifespan. Furthermore,diabetes and hypertension are associated withneurodegenerative processes and hippocampal atro-phy. In the present investigation we specificallyconsidered their effect. We found that although theassociations between SMD and hippocampal vol-ume/atrophy were somewhat weaker after control-ling for anxiety and depression symptomatology ontheir own (results not shown) or in conjunction todiabetes and hypertension, they remained significantin most instances. Importantly, those with SMD hadlower anxiety and depression symptomatology, sug-gesting that SMD without anxiety and/or depressionshould be considered particularly seriously.It is also interesting to note that those with SMD

had on average a higher level of education, did notdiffer in their APOE genotype frequency, and had asimilar physical health profile compared with thosewithout SMD, which further highlights the fact thatSMD, in the context of normal physical and mentalhealth, may be of particular significance in early oldage. APOE genotype is associated with hippocampalvolume and atrophy in most analyses, consistent withsome but not all previous findings in both AD pa-tients and healthy subjects.28,40e42 We found, how-ever, that hippocampal volume was significantlyassociated with SMD when controlling for the effectof APOE genotype, suggesting an independent effect.This study has a number of strengths, including

manual tracing of the hippocampus, a large samplesize, a longitudinaldesign, and theuseof a community-based narrow-age sample which reduces the risk ofcohort bias. There were also a number of limitations,however. Scanning parameters differed at baseline andfollow-up and although this difference cannot explainthe pattern of result observed (as all participants were

Am J Geriatr Psychiatry -:-, - 2014

Cherbuin et al.

scannedwith the samemethodology at eachwave), itcould have influenced the magnitude of our findings.In addition, SMD was assessed in a relatively crudeway and although this is the norm in this area ofresearch, and some have presented the simplicity andrelative non-threatening nature of such surveys as anadvantage,2 more fine-grained assessment of SMDmay provide important additional information. Inaddition, although the sample size was large for astudy of this type it may not have provided sufficientstatistical power in sub-analyses to detect sex andAPOE genotype interactions. For example, if indeedhippocampal atrophy precedes SMD, it would havebeen expected that a significant association would bedetected between SMD present at follow-up only andhippocampal atrophy. No such association wasdemonstrated. This was possibly because the smallnumber of participants presenting with SMD atfollow-up only (N ¼ 17) did not provide sufficient

Am J Geriatr Psychiatry -:-, - 2014

statistical power to more convincingly inform thisquestion. Alternatively, it is also possible that SMDand hippocampal atrophy follow a more concurrentdevelopment. This question will need further atten-tion in future longitudinal investigations.

The authors are grateful to Peter Butterworth, An-thony Jorm, Helen Christensen, Chantal R�eglade-Meslin,Jerome Maller, Patricia Jacomb, Karen Maxwell, and thePATH project interviewers. The study was supported byNational Health and Medical Research Council grants973302, 179805, 157125, 1063907, and ARC grant1063907. Nicolas Cherbuin is funded by ARC ResearchFellowship 120100227 and Kaarin Anstey by NHMRCResearch Fellowship 1002560. This research was partlyundertaken on the National Computational Infrastructure(NCI) facility in Canberra, Australia, which is supportedby the Australian Commonwealth Government.

The authors have reported no conflicts of interest.

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