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NeuroImage 112 (2015) 364374

Contents lists available at ScienceDirect

NeuroImage
journal homepage: www.elsevier.com/locate/ynimg

Review

A systematic review and meta-analysis of longitudinal hippocampal


atrophy in healthy human ageing,,,
Mark A. Fraser , Marnie E. Shaw, Nicolas Cherbuin
Centre for Research on Ageing, Health and Wellbeing, Florey, Building 54, Mills Road, Australian National University, Canberra, ACT 2601, Australia

a r t i c l e

i n f o

a b s t r a c t
Introduction: This review aimed to produce hippocampal atrophy rate estimates from healthy ageing studies as
well as control samples from observational studies across the adult lifespan which can be used as benchmarks
to evaluate abnormal changes in pathological conditions.
Methods: The review followed PRISMA guidelines. PUBMED (to February 2014) was searched for longitudinal
MRI studies reporting hippocampal atrophy or volume change in cognitively healthy individuals. Titles were
screened and non-English, duplicate or irrelevant entries were excluded. Remaining record abstracts were
reviewed to identify studies for full text retrieval. Full text was retrieved and screened against inclusion/exclusion
criteria. Bibliographies and previous reviews were examined to identify additional studies. Data were
summarised using meta-analysis and age, segmentation technique and study type were tested as potential moderators using meta-regression. It was hypothesised that population studies would produce higher atrophy rates
than clinical observational studies.
Results: The systematic search identied 4410 entries and 119 studies were retrieved with 58 failing selection or
quality criteria, 30 were excluded as multiple reports and 3 studies were unsuitable for meta-analysis. The remaining 28 studies were included in the meta-analysis, n = 3422, 44.65% male, 11,735 person-years of followup, mean age was 24.50 to 83 years. Mean total hippocampal atrophy for the entire sample was 0.85% per year
(95% CI 0.63, 1.07). Age based atrophy rates were 0.38% per year (CI 0.14, 0.62) for studies with mean age
b 55 years (n = 413), 0.98% (CI 0.27, 1.70) for 55 to b 70 years (n = 426), and 1.12% (CI 0.86, 1.38) for
70 years (n = 2583). Meta-regression indicated age was associated with increased atrophy rates of 0.0263%
(CI 0.0146, 0.0379) per year and automated segmentation approaches were associated with a reduced atrophy
rate of 0.466% (CI 0.841, 0.090). Population studies were not associated with a signicant effect on atrophy. Analyses of 11 studies separately measuring left and right hippocampal atrophy (n = 1142) provided little
evidence of laterality effects. While no study separately reported atrophy by gender, a number tested for gender
effects and 2 studies reported higher atrophy in males.
Conclusions: Hippocampal atrophy rates increase with age with the largest increases occurring from midlife onwards. Manual segmentation approaches result in higher measured atrophy rates.
2015 Elsevier Inc. All rights reserved.

Article history:
Received 25 October 2014
Accepted 14 March 2015
Available online 20 March 2015
Keywords:
Hippocampus
MRI
Longitudinal
Ageing
Epidemiology
Controls

Contents
Introduction . . . . . . . . . . . .
Methods . . . . . . . . . . . . .
Search strategy . . . . . . . .
Inclusion and exclusion criteria
Data extraction . . . . . . . .

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Statistical analysis: Mark Frasera.


Disclosure: The authors have reported no conicts of interest.
Disclosures: Mark Fraser reports no disclosures. This study is not industry sponsored.
Contributions: Mr. Fraser contributed to the design of the study, conducted all statistical analyses, and managed all aspects of manuscript preparation and submission. Dr. Shaw
provided methodological input and theoretical expertise, and contributed to writing and editing of the manuscript. Dr. Cherbuin contributed to the design of the study and the statistical
analyses, provided methodological input and theoretical expertise, and contributed to writing and editing of the manuscript.
Corresponding author. Fax: +61 2 6125 1558.
E-mail address: mark.fraser@anu.edu.au (M.A. Fraser).

http://dx.doi.org/10.1016/j.neuroimage.2015.03.035
1053-8119/ 2015 Elsevier Inc. All rights reserved.

M.A. Fraser et al. / NeuroImage 112 (2015) 364374

Statistical analysis . . . . . .
Missing data . . . . . . . . .
Meta-analysis . . . . . . . .
Reporting bias . . . . . . . .
Results . . . . . . . . . . . . . .
Meta-analysis . . . . . . . .
Reporting bias . . . . . . . .
Discussion . . . . . . . . . . . .
Laterality effects . . . . . . .
Moderators & heterogeneity . .
Reporting bias . . . . . . . .
Dropouts . . . . . . . . . .
Gender . . . . . . . . . . .
Limitations of the study . . . .
Conclusions . . . . . . . . .
Acknowledgments . . . . . . . .
Appendix A.
Supplementary data
References . . . . . . . . . . . .

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Introduction
The hippocampus plays an essential role in memory function, goal
selection, and mood regulation. Hippocampal volume changes have
been associated with neurological conditions including Alzheimer's
disease (Jack et al., 2000; West et al., 1994), Parkinson's disease
(Camicioli et al., 2003), Huntington's disease (Majid et al., 2011),
epilepsy (Liu et al., 2001), schizophrenia (Wang et al., 2008), and
depression (Arnone et al., 2012; Steffens et al., 2011). Hippocampal
volume changes also occur across the typical adult lifespan (Raz et al.,
2010). However, the magnitude of normal hippocampal age related
change is unclear and this presents a challenge when evaluating
abnormal changes in pathological conditions such as Alzheimer's
disease.
In order to accurately estimate hippocampal change in pathological
conditions it is critical that reliable and precise estimates be available
for generally healthy populations of different ages. This review
has focused on estimates from longitudinal studies in preference to
cross-sectional estimates because cross-sectional estimates can be confounded by individual subject baseline volumes. Studies where both
longitudinal and cross-sectional analyses were used indicate that
cross-sectional studies are less able to detect hippocampal volume
change effects (Du et al., 2006; Raz et al., 2005; Ridha et al., 2006).
There is now a substantial body of research investigating longitudinal
hippocampal volume change across multiple domains encompassing
the entire adult lifespan. The domain covering younger individuals focuses on neurodegenerative conditions that become apparent in adolescence or young adulthood such as schizophrenia, temporal lobe epilepsy
and mood disorders (Geuze et al., 2005). The studies in these younger
age groups tend to have small sample sizes and small effect sizes
(b0.5% annualised atrophy). A second domain of research focuses on
conditions that become apparent later in life including AD, other forms
of dementia, Parkinson's disease, Huntington's disease and other age related pathologies (Geuze et al., 2005). Hippocampal atrophy rates increase prior to the appearance of AD symptoms and continue to
increase as the disease progresses (Fox et al., 2001; Ridha et al., 2006;
Whitwell et al., 2007). Given that the incidence of dementia is increasing
as populations worldwide age (Fratiglioni et al., 1999), a growing body
of research on dementia with many large samples primarily focused
on people over 50 years of age has emerged. In a review of AD studies,
Barnes et al. (2009) estimated annualised atrophy rates of 4.66% per
year (95% CI 3.92, 5.40) for AD subjects and 1.41% per year (95% CI
0.52, 2.30) for healthy elderly controls. A third domain investigates
changes in healthy ageing in normal individuals. Available evidence suggests that hippocampal volumes change throughout adult life in a nonlinear manner (Raz et al., 2010), with hippocampal volume being

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relatively stable in young adulthood. There appears to be a critical


point after 50 years of age when the rate of hippocampal atrophy accelerates to 0.80.9% per year with hippocampal volumes declining steadily
thereafter with age (Fjell et al., 2013; Schuff et al., 2012).
The aim of this review was rstly to provide age-specic data on the
rates of hippocampal atrophy across the adult lifespan which are as representative as possible of the normal population. The second aim was to
investigate the effects of segmentation techniques on atrophy measurements. Thirdly, we sought to investigate the impact of study design on
measured atrophy rates. It was hypothesised that population studies
would produce higher atrophy rates due to less restrictive healthbased exclusion criteria than control groups used in clinical investigations. Our nal goal was to summarise other ndings pertinent to normal ageing such as gender and laterality effects.
Methods
This systematic review and meta-analysis followed the Preferred
Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)
2009 guidelines without prior publication of the review protocol
(Moher et al., 2009). The literature search was based on predetermined search terms, inclusion, exclusion and quality criteria that
included the assessment of bias at the study level. The approach used
for data collection, conrmation and data simplications are fully described. The risk of bias across studies was assessed and the post hoc
analyses are clearly identied.
Search strategy
PUBMED (1950 to February 2014) was searched using the terms:
(hippocampus or hippocamp*) and (longitudinal or atrophy or change
or volume or volumetry or volumetric) and humans and (magnetic resonance imaging or MRI or neuroimaging). All returned titles were
screened and any non-English, duplicate or clearly irrelevant entries
were excluded. Next, the remaining record abstracts were reviewed to
identify studies for full text review. Full text and supplementary material of potential studies were retrieved for screening against inclusion and
exclusion criteria. Bibliographies of retrieved reports and previous reviews covering hippocampal atrophy were examined to identify additional studies for inclusion.
Inclusion and exclusion criteria
Published studies were included if they met the following criteria:
(1) were an empirical study; (2) measured adult human hippocampal
volume from in-vivo structural MRI images at more than one time

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M.A. Fraser et al. / NeuroImage 112 (2015) 364374

point; and (3) included at least one group of healthy participants, cognitively normal or derived from a population sample. Studies were excluded if they (a) reported exclusively on clinical treatment groups
(including placebo treatments); (b) were case studies or samples with
less than twenty participants; (c) had an MRI follow-up period of less
than twelve months; (d) the age or gender of the sample could not be
ascertained; or (e) did not provide information to allow calculation of
hippocampal atrophy. Studies meeting the inclusion and exclusion
criteria were assessed for quality using a checklist adapted from previous reviews and the Cochrane collaboration handbook (Anstey et al.,
2011; Harlein et al., 2009; JPT and Green, 2011; Stroup et al., 2000).
Mandatory quality criteria were a prospective design, a dened study
period, specication of population characteristics, standardised data
collection and the absence of signicant bias in the sample selection.
For example, samples that had been constructed to increase the proportion of participants with a family history of AD were excluded.

Data extraction
Data were extracted by two of the authors (MF and MS) and discrepancies were resolved by consensus. Where a particular sample was reported in multiple studies, the study that best t the selection criteria
and provided information in the format most suitable for metaanalysis was included and other studies were excluded. Studies that
measured hippocampal volume using manual techniques were
classied as using Manual segmentation and studies that used
automated or semi-automated segmentation techniques were classied
as using Automated segmentation. Follow-up periods were converted
to years and atrophy measures were converted to % per year with
positive atrophy representing a loss of hippocampal tissue. Variance
information was converted to standard deviations (SD). Where
atrophy was not provided, it was calculated using the formula:
Atrophy = ((volume_time1 volume_time2) / volume_time1) /
(time1 time2). Total atrophy was calculated by averaging left and
right atrophy weighted by left and right hippocampal volumes. Authors
of the selected studies were contacted via email to gain additional information or seek clarication where required. The authors contacted provided additional volume, atrophy or correlation information to enable
studies to be included in the meta-analyses.
Where studies provided separate atrophy rates for age based subsets, the age based rates were included separately. For studies where a
normal sample had been split into sub-samples by category such as
APOE variant and the atrophy information was only available at the
sub-sample level, a single weighted atrophy rate was calculated from
the sub-sample information. Where studies provided separate atrophy
rates for consecutive time points, a single mean atrophy rate was
calculated.

Meta-analysis
A random-effects model using a restricted maximum likelihood estimator (REML) was used for all meta-analyses. A random effects model
was chosen based on the assumption that included studies are heterogeneous because they sample populations with different characteristics
using a range of methodologies and therefore one cannot assume that
there is a single effect size (Borenstein et al., 2011). A random effects
meta-analysis estimates the mean of a distribution of effects rather
than estimating a unique effect (Borenstein et al., 2011). We assessed
heterogeneity across studies with the Q statistic (with p b .10 being suggestive of signicant heterogeneity) and the I2 statistic (values of 25%,
50% and 75% were indicative of low, medium, and high heterogeneity).
Separate meta-analyses were performed for total, left and right hippocampal atrophy. Sensitivity analysis was performed to assess the impact
of including SDs imputed with the multiple imputation procedure.
The impact of age on the observed atrophy rate was explored
through a meta-analysis stratied by age groups. The stratication procedure consisted of grouping studies such that it maximised the number
of age groups, containing at least 3 samples, where most of the participants from those samples would t within the age range of the group.
The distribution of samples in terms of mean age and SD was examined
to identify the number of age based groups that could be practically implemented for total, left and right hippocampal atrophy. For each age
group, the mean and SD of the included samples were used to estimate
the proportion of participants that would be fall below, within and
above the group age range. Sensitivity analysis was used to determine
group boundaries that would optimise the proportion of the sample
participants included within the groups.
Meta-regression was used to investigate the inuence of the moderators of sample type (population vs clinical), segmentation approach
(manual vs automated) and age using linear mixed-effects models
(Borenstein et al., 2011; Viechtbauer, 2010). A number of additional
non-linear meta-regression models using quadratic and cubic terms
were tested post hoc but they provided a poorer t than the linear
models.
Reporting bias
Studies that report signicant results are more likely to be published
than studies resulting in non-signicant outcomes (Song et al., 2010)
and this is known to bias the results of meta-analytic reviews. It is therefore important to formally assess publication bias and interpret results
accordingly. Reporting bias was assessed by visual inspection of funnel
plots which are scatterplots where the effect size is plotted against the
standard error of the effect size. Asymmetry of the funnel plots may
be an indication of reporting bias. The trim and ll method (Duval and
Tweedie, 2000a,b) was used to estimate the number of studies that
may be missing from the meta-analysis and to estimate adjusted effect
sizes.

Statistical analysis
Results
R version 3.1.1 (R Core Team, 2014) was used for statistical analysis.
The Amelia II R package version 1.7.2 was used for multiple imputations
(Honaker et al., 2011) and meta-analyses were performed using the
Metafor version 1.9-4 R package (Viechtbauer, 2010).

Missing data
In a few instances (n = 3) where atrophy SDs were missing, it was
possible to impute them from other published information (JPT and
Green, 2011). In other cases (total hippocampus n = 6, left/right hippocampi n = 3), missing SDs were estimated by multiple imputation using
an expectation-maximisation (EM) bootstrapping method with 5 imputations using Amelia II (Thiessen Philbrook et al., 2007).

The search identied 4410 titles, bibliography searches identied


another 11 titles and a previous review (Barnes et al., 2009) yielded
one title (Kaye et al., 2005). Of 119 retrieved studies, 58 did not meet inclusion, exclusion or quality criteria; 14 were not longitudinal, 21 did
not measure hippocampal volume change, 10 had biased samples, 6
had b20 participants, 3 had no age or gender, 3 had b12 month follow
up, and 1 was an autopsy study. A further 30 studies were excluded
due to multiple reporting of the same data, 16 of which used samples
from the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset.
Of 31 studies that met the inclusion and exclusion criteria, 16 related
to mild cognitive impairment (MCI) or dementia, 8 were ageing or
population studies, 3 related to schizophrenia, 2 to depression, 1 to
Huntington's disease and 1 to total life experience. Fig. 1 shows the

M.A. Fraser et al. / NeuroImage 112 (2015) 364374

367

automated segmentation approaches. The delineation of the hippocampus in most of the automated studies differed from the manually segmented studies by including the tail past the crus of the fornix and
excluding the mbria and alveus. A number of studies tested for gender
effects and two found increased atrophy in males; Cherbuin et al.
(2012) found greater hippocampal atrophy and Driscoll et al. (2009)
found greater age related temporal lobe atrophy.
Meta-analysis

Fig. 1. Screening and selection process for studies included in the meta-analysis.

process used for inclusion in the review. The reviewed studies are
summarised in Table 1. Additional information including imaging parameters and segmentation protocols are described in Supplementary
tables S1S4.
Quality ratings of included studies met the following criteria: denition of exposure variable and outcome, prospective design, specication
of population characteristics, description of study period, description of
the sampling procedure, standardised and described data collection,
multivariate statistics described, and reproducibility. Ten studies had
more than 100 participants across all groups. Dropout rates varied
with 16 studies reporting a dropout rate of less than 20%, 9 studies
reporting greater than 20%, 1 study did not include dropout information, 4 studies selected participants that had two MRI scans from larger
prospective datasets and 1 study invited participants from existing
studies to have a follow-up scan.
Manual segmentation was used in 19 studies. The anatomical denitions used in manually segmented studies were generally consistent in
including the dentate gyrus, hippocampus proper (CA1 through CA4),
subiculum, mbria and the alveus. All manually segmented studies included the head, the body and the tail up to the crus of the fornix except
for Kaye et al. (2005) who only measured the hippocampus body and
Whitworth et al. (2005) who included some amygdala tissue in the segmentation. Twelve studies used a range of different automated or semi-

Of the 31 studies reviewed, 28 were included in the meta-analysis.


Two all-male studies (MacLullich et al., 2012; Whitworth et al., 2005)
were excluded to avoid gender bias and Callisaya et al. (2013), with
an annualised atrophy rate of 9.98%, was identied as an outlier during
meta-analysis and excluded. The remaining 28 studies covered 3422
participants of whom 1469 (44.65%) were male.
The 28 studies provided 35 samples with estimates for total hippocampal atrophy. Visual inspection of the distribution of the samples'
mean ages suggested that three age groups; young, youngold and
oldold, could be implemented. Sensitivity analysis was used to choose
the optimum break points (50 versus 55 years and 70 versus 75 years)
between the age groups. The analysis yielded the following three age
groups; 1) less than 55 years represented 92% of 413 participants in
12 samples; 55 years to less than 70 years represented 87% of 426 participants in 7 samples; and 70 years and over represented 78% of 2583
participants in 16 samples. With fewer studies measuring left and
right hippocampal atrophy, the distribution of sample mean ages suggested only two age groups. Sensitivity analysis was used to choose
the optimum break point (50 versus 55 years) between the groups.
The analyses yielded two age groups; 1) less than 55 years representing
88.0% of 225 participants in 4 samples and 2) 55 years and over
representing 100% of 917 participants in 7 samples. Excluding the multiple imputed samples did not signicantly alter the atrophy estimates.
The results of the meta-analyses are shown in Table 2. Forest plots with
age based subsets for total, left and right hippocampal atrophy are
shown in Figs. 24.
Signicant heterogeneity was found in all meta-analyses performed
with p b 0.0001 for tests of homogeneity in effects. The proportion of observed variance between studies (I2) that is real (i.e. not related to random error) was high in all but one of the age groups with I2 ranging
from 68.75% to 99.99% and the proportion of heterogeneity tended to
be higher in older age groups. A mixed effects model using moderators
of age, segmentation technique and sample type indicated that age and
segmentation type were signicant moderators of annualised atrophy
and sample type was not a signicant moderator. A second model limited to the signicant moderators estimated that age and segmentation
type accounted for 42.78% of the heterogeneity in total hippocampal atrophy (Table 3). The test for residual heterogeneity was signicant
Q(32) = 1976.57, p b 0.0001, indicating that other moderators are
inuencing the atrophy rate. The impact of segmentation approach
was investigated post hoc using separate meta-regression models for
manual and automated studies (Table 3, Models 34). The different predicted atrophy rates for manual and automated segmentation technique
by age are plotted in Fig. 5.
Reporting bias
The funnel plot for studies reporting on total hippocampal atrophy
(Fig. 6) is reasonably symmetrical and no missing studies were identied using the trim and ll method, suggesting the absence of publication bias (Duval and Tweedie, 2000a,b). The large number of the
points falling outside the funnel in Fig. 6 is likely to be due to the significant heterogeneity between studies. In the absence of heterogeneity,
95% of the studies would be expected to fall within the funnel area.
The funnel plots for studies reporting left and right hippocampal atrophy (Figs. 78) were less symmetrical and the trim and ll method

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M.A. Fraser et al. / NeuroImage 112 (2015) 364374

Table 1
Studies included in the review.
Study

Group

Male %

Age mean
(SD)

Time
(SD)

Segmentation

Barnes et al. (2008)


Callisaya et al. (2013)
Cherbuin et al. (2012)
Crivello et al. (2010)
den Heijer et al. (2010)
Driscoll et al. (2009)
Du et al. (2004)
Frodl et al. (2008)
Jack et al. (1998)
Jack et al. (2004)d
Kaye et al. (2005)
Koolschijn et al. (2010)
Liu et al. (2003)

NC
Population
Population
Population
Population
Population
CN
NC
NC
CN-stable
CN
NC
1434
35 to 54
Over 54
Healthy
NC
Normal
Young b50
Old 50+
Healthy
Controls
Population
3039 years
4049 years
5059 years
6069 years
7084 years
Controls
Controls
Healthy
NCI-S
Healthy
CN
NC
NC
Population
NC

20
225
249
1186
244
120
25
30
24
40
88
113
44
37
9
41
22
58
32
40
30
25
281
8
10
10
6
5
20
199
72
26
37
26
62
20
204
20

50
56.4
57
36.7
49
60.8
44
36.7
33.3
42.5
47.7
67.3
59.1
45.9
66.7
100
31.8
46.6

46.7
36
42.3
50
50
50
50
25
50
53.3
19.4
19.2
43.2
46.2
54.8
55
54.4
100

69 (7)
71.4 (6.8)
62.6 (1.4)
72.3 (3.9)
73.5 (7.9)
70.6 (6.1)
76 (7.8)
43.6 (13.1)
81.0 (3.8)
79 ()
83.0 (7.0)
35.4 (12.3)
24.5 (6.6)
44.5 (5.7)
67.9 (6.4)
67.3 (1.3)
40.1 (12.2)
74.1 (6.7)
39.4 (8.3)
63.1(7.0)
63.1 (7.0)
46.5 (10.2)
72.3 (3.8)
36.1 (2.5)
45.6 (2.9)
53.9 (3.5)
62.7 (2.3)
76.8 (5.5)
45.8 (6.8)
76 (5.1)
69.4 (6.2)
78 (6)
70.3 (5.8)
73 (7)
36.2 (14.5)
75.1 (3.7)
78.4 (5.0)a
31.5 (4.9)j

1 (01)
2.55 (0.41)
4 (0.21)
4 ()
3.4 (0.3)
6.02 (2.91)
2 (0.7)
3 (0)
1.96 (0.75)
4.3 () (2.55.2)e
2.04 (1.42)
4.94 (0.32)
3.57 (0.13)
3.53 (0.08)
3.53 (0.09)
6 ()
1 (0.1)
3.4 (1.4)
5.27 (0.3)

Manual
Manual
Manual
Automated
Automated
Automated
Automated
Manual
Manual
Manual
Manual
Manual
Manual

MacLullich et al. (2012)


Majid et al. (2011)
Mungas et al. (2005)
Raz et al. (2005)
Raz et al. 2010
Ridha et al. (2006)
Samieri et al. (2012)
Scahill et al. (2003)

Schott et al. (2003)


Schott et al. (2010)
Steffens et al. (2011)
Stoub et al. (2010)
Valenzuela et al. (2008)
Wang et al. (2003)
Wang et al. (2008)
Wang et al. (2009)
Whitwell et al. (2012)i
Whitworth et al. (2005)

Atrophy % per year


Total

2.61
1.5 (0.8)
4 ()
1.58 (1.19)
1.83 (0.87)
1.91 (1.11)
2.07 (1.21)
0.98 (0.42)
1.41 (0.8)
1 ()
2 ()
5
3 ()
2.2 () 1.02.6e
2.24 (5.8)
1.88 () 0.892.9e
1.25 ()
3.7 (1.63)

Manual
Automated
Automated
Manual
Manual
Manual
Automated
Manual

Manual
Automated
Automated
Manual
Manual
Automated
Automated
Manual
Automated
Manual

Left

0.28 (0.93)
9.86 (4.17)a
2.03 (0.033)
1.204 (2.5402)b
0.51 (0.43)
0.32 (0.049)a
0.8 (1.7)
0.20c (1.65)
1.55 (1.38)
1.4 (0.7)f
2.2 (6.0)
0.8043 (.0267)a
0.11 (3.34)
0 (2.31)
0.64 (2.78)
0.16 ()
0.02 (0.72)
1.1 (1.4)
0.48 (0.83)a
1.04 (0.797)a
2.18 (2.46)
0.31 (1.25)
0.9455 (0.6841)a
0.75 (1.25)
0.5 (0.375)
1.05 (0.475)
0.875 (0.5875)
1.9375 (1.7375)
0.12c (1.83)
1.01 (1.72)
0.84 (5.9)h,a
1.4188 (0.2444)a
1.98 (3.92)b
2.34 (1.853)
0.105c (1.84)
1.0 (0.07)
0.50 (2.22)a
1.25 ()

Right

0.02 (1.25)

0.52 (1.37)

2.56 (0.034)a

1.46 (0.036)a

0.52 (0.60)

0.51 (0.88)

1 (2.6)
0.31 (2.15)

0.6 (2.5)
0.09 (2.36)

0.8028 (.0285)a

0.8054 (.0285)a

0.27 (1.94)g

0.04 (1.90)g

1.0 (0.8)

0.9 (0.8)

0.45 (1.63)

0.21 (3.00)

1.07 (7.19)h

0.63 (6.28)h

1.82 (2.04)
0.26 (2.15)

2.50 (2.03)
0.03 (2.50)

1.95 (3.12)

0.53 (3.21)

NC = normal controls; CN = cognitively normal; CN-stable = CN that does not progress to MCI or AD; NCI-S = no cognitive impairment at baseline, stable.
Multiply imputed SDs are shown in italics.
a
Personal communication with author.
b
Values pooled from subsets.
c
Calculated from left and right atrophy.
d
CN split into subsets of stable & converters only stable subset included in analysis.
e
Median plus range.
f
Source Barnes et al. (2009).
g
SD imputed using p-value.
h
Atrophy calculated from volume change.
i
Included MCSA sample only.
j
Age at follow-up.

Table 2
Meta-analysis estimates of total, left and right hippocampal atrophy rates with age based subsets.
Qp

T2

I2

1.07
0.62
1.38
1.70
1.38

b.0001
b.0001
b.0001
b.0001
b.0001

0.36
0.12
0.31
0.76
0.22

0.6
0.34
0.56
0.87
0.47

99.96
85.45
99.92
96.60
98.75

0.04
0.45
0.14

1.23
0.76
1.75

b.0001
b.0001
b.0001

0.89
0.30
1.05

0.94
0.55
1.02

99.99
84.45
99.75

0.25
0.21
0.31

1.15
0.87
1.52

b.0001
b.0001
b.0001

0.45
0.19
0.55

0.67
0.43
0.74

99.99
68.75
99.30

Description

Age

Atrophy %/yr

s.e.

95% CI

Total hippocampus
Young: b55 years
Old: 55+ years
55 to b70 years
70+ years

35
12
23
7
16

3422
413
3009
426
2583

68.59
39.53
72.58
64.24
73.95

0.85
0.38
1.12
0.98
1.12

0.11
0.12
0.13
0.37
0.13

0.63
0.14
0.86
0.27
0.86

Left hippocampus
b55 years
N55 years

11
4
7

1142
225
917

64.34
40.06
70.29

0.64
0.16
0.94

0.30
0.31
0.41

Right hippocampus
b55 years
N55 years

11
4
7

1142
225
917

64.34
40.06
70.29

0.70
0.33
0.92

0.23
0.28
0.31

k = number of samples or sub-samples included in analysis; s.e. = standard error; Qp = p-value for the signicance test of the Q statistic; T2 = heterogeneity = estimated variance of true
effects; T = estimated standard deviation of true effects; I2 = proportion of observed variance (heterogeneity) that is real.

M.A. Fraser et al. / NeuroImage 112 (2015) 364374

369

Fig. 2. Random effects model of total hippocampal atrophy with age based subsets. Studies are ordered by mean age.

estimated one missing study for the left hippocampus and three missing
for the right hippocampus, inclusion of the missing studies produced
adjusted estimates for left hippocampal atrophy of 0.74% per year
(95% CI 0.15, 1.33) and right hippocampal atrophy of 0.96% per year
(95% CI 0.50, 1.42). The adjusted estimates should be treated with caution for two reasons. Firstly the estimated missing studies had very large
effect sizes and are therefore unlikely to result from reporting bias, and
secondly, the estimates produced by the trim and ll method have been
shown to be unreliable in the presence of signicant heterogeneity as
observed in the present results (Peters et al., 2007; Terrin et al., 2003).

Discussion
The aim of this review was to estimate hippocampal atrophy rates
across the adult lifespan in cognitively normal individuals and to investigate the impact of age, sample type and segmentation approach on observed atrophy rates.
Overall, the estimated rate of total hippocampal atrophy across all
studies of 0.85% per year was consistent with previous longitudinal
ndings and higher than the atrophy rates of 0.280.35% per year (Raz
et al., 2005; Raz et al., 2004b; Scahill et al., 2003) reported in cross-

Fig. 3. Random effects model of left hippocampal atrophy with age based subsets. Studies are ordered by mean age.

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M.A. Fraser et al. / NeuroImage 112 (2015) 364374

Fig. 4. Random effects model of right hippocampal atrophy with age based subsets. Studies are ordered by mean age.

sectional studies. By bringing together the results for control participants in a range of research domains we were able to show that there
is a small yet signicant rate of atrophy from young adulthood to middle
age of 0.38% per year. In contrast, individual studies that have measured
hippocampal change in younger age groups have provided equivocal
evidence of atrophy with many nding non-signicant hippocampal
volume changes, likely due to insufcient power to detect small effects.
Hippocampal atrophy rates increase with age (Du et al., 2006) and
this meta-analysis further demonstrates that the most signicant atrophy occurs from midlife onwards. The hippocampal atrophy rate increased to 0.98% per year for studies with a mean age of 55 to less
than 70 years. The estimate from this transition group was the least precise estimate due to the smaller number of studies included. The rate of
atrophy further increased to 1.12% per year in the 70 years and older age
group. While the estimates for the older age groups were lower than the

rate of 1.41% per year estimated in a previous review, the difference was
not signicant (Barnes et al., 2009). The pattern of atrophy change with
age is consistent with previous cross-sectional and longitudinal ndings
reporting a non-linear trajectory in hippocampal ageing (Fjell et al.,
2013; Raz et al., 2010; Schuff et al., 2012), but with few samples covering middle age, it was not possible to model the critical point that is believed to occur after the age of 50 years (Fjell et al., 2013). More
longitudinal research covering this critical time should be undertaken.
Laterality effects
The estimated atrophy rates for the left and right hippocampus were
consistent with total hippocampal atrophy rates. There was little evidence of laterality differences in the atrophy estimates produced by
the meta-analysis. This nding is of particular interest because a

Table 3
Mixed effects models of hippocampal atrophy rates. Model 1: age, segmentation technique and sample type; Model 2: age and segmentation technique; Model 3: age effect on studies
using manual segmentation; Model 4: age effect on studies using automated segmentation.
k
Model 1
Intercept
Age
Segmentation
Sample type

35

Model 2
Intercept
Age
Segmentation

35

Model 3
Intercept
Age

23

Model 4
Intercept
Age

12

r2

0.1529
0.0375
0.1155
0.6857

0.4558

41.84

1.318
0.0146
0.8413

0.1129
0.0379
0.0899

0.4521

42.78

0.0976
b.0001

1.5798
0.0142

0.1325
0.0425

0.4542

45.26

0.3170
0.0494

2.2862
0.0001

0.7408
0.0438

0.4827

29.98

Coef

s.e.

95% CI

0.5720
0.0256
0.5222
0.1878

0.3699
0.0061
0.2075
0.2540

1.5466
4.2053
2.5165
0.7394

0.1220
b0.0001
0.0119
0.4597

1.2970
0.0136
0.9289
0.3100

0.6026
0.0263
0.4656

0.365
0.006
0.1917

1.6508
4.414
2.429

0.0988
b.0001
0.0151

0.7237
0.0284

0.4368
0.0072

1.6567
3.9188

0.7727
0.0219

0.7722
0.0112

1.0006
1.9651

k = number of samples or sub-samples included in analysis; s.e. = standard error; = standard deviation of true effects; r2 = proportion of observed dispersion accounted for by the
model.

M.A. Fraser et al. / NeuroImage 112 (2015) 364374

371

Fig. 7. Funnel plot of left hippocampal atrophy using trim and ll method. Filled circles
represent studies included in the meta-analysis. Open circles represent possible missing
studies.

There was considerable heterogeneity between studies and the


moderators of age and segmentation technique accounted for just

under half of the heterogeneity. Unsurprisingly, age had the largest effect, accounting for most of the explained heterogeneity. Given that
many studies had wide age ranges, exceeding 25 years in some cases,
it is possible that age may have a greater moderating effect than quantied by the meta-regression. Another salient feature of this metaanalysis is that heterogeneity between studies was higher in studies
with a mean age greater than 55 years. This is probably due to chronic
disease and non-clinical brain changes which become more prevalent
in ageing. However, more targeted research is required to understand
the factors driving increased variability in older samples.
The other signicant moderator of heterogeneity identied was the
segmentation technique used to measure hippocampal volume. The
meta-regression suggested that automated segmentation results in
lower atrophy rate estimates. It is possible that automated approaches
may include some non-hippocampal tissue that has a lower rate of atrophy than hippocampal tissue (Wenger et al., 2014). Indeed, Cherbuin
et al. (2009) found that the hippocampal segmentation implemented
in Freesurfer produced signicantly larger volumes compared to

Fig. 6. Funnel plot of total hippocampal atrophy using trim and ll method. Filled circles
represent studies included in the meta-analysis. Open circles represent possible missing
studies.

Fig. 8. Funnel plot of right hippocampal atrophy using trim and ll method. Filled circles
represent studies included in the meta-analysis. Open circles represent possible missing
studies.

Fig. 5. Meta-regression of atrophy rate and mean age. The size of circles is proportional to
the weight given to the study. Larger studies and more precise studies are given more
weight in the meta-analysis. Magenta circles represent studies using manual segmentation and blue circles represent studies using automated segmentation. The magenta line
is the predicted mean atrophy rate change with age with manual segmentation
(Model 3) and the blue line represents the predicted mean atrophy rate with age for automated segmentation (Model 4).

number of studies have suggested earlier and faster atrophy in the left
hippocampus. Consequently if this effect is not present in generally
healthy individuals it may be more indicative of developing neurodegenerative pathology which has been reported to be asymmetrical
(Cherbuin et al., 2010; Thompson et al., 2003).
Moderators & heterogeneity

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M.A. Fraser et al. / NeuroImage 112 (2015) 364374

manual segmentation of the same images. This explanation would also


be consistent with ndings by Mulder et al., (2014) indicating that manual segmentation produced higher atrophy rates than Freesurfer
(Reuter et al., 2012) or FIRST (Patenaude et al., 2011). Differential atrophy rates between the hippocampal head and tail could also contribute
to the different atrophy rates between manually segmented studies (excluding the tail) and the studies using automated segmentation (including the tail) consistent with the Wang et al. (2003) ndings that atrophy
was mostly conned to the head of the hippocampus and subiculum in
non-demented controls. One possible implication of these results is that
specic atrophy benchmarks may be required for segmentation techniques relying on substantially different methods, protocols or
landmarks.
The hypothesis that population studies produce higher atrophy rates
due to less restrictive exclusion criteria was not supported. This may be
because the exclusion criteria for the population samples were similar
to the other studies in excluding participants with neurological and severe chronic conditions.
Reporting bias
Reporting bias was not expected given that this review utilised samples where the decision to publish or not publish was unlikely to be inuenced by the atrophy rate of control groups. There was no evidence of
reporting bias for total hippocampal atrophy. However, there was an indication of missing studies reporting left and right hippocampal atrophy. If
these missing studies had non-signicant effect sizes, it may be an indication of reporting bias. However, in this case all three missing studies had
signicant effect sizes. While the adjusted estimates for left and right atrophy, after inclusion of the estimated missing studies, did not represent
a signicant change, they did move the estimates closer to that of the total
hippocampal atrophy.
Dropouts
In longitudinal studies carried out over many years there is likely to be
a high dropout rate, especially when participants are over 60 years old.
Since drop out tends to be highest in the frail and sick, it could bias the results of studies examined. Most of the studies reported the characteristics
of dropouts in comparison to those that did not drop out. In older cohorts,
the dropouts tended to be older and less healthy than the participants
who were not lost to follow-up, consequently the atrophy rates in the
older cohorts may be understated.

Limitations of the study


This review took a novel approach of utilising control samples from a
range of research areas including schizophrenia, AD and ageing to enable
the analysis of studies covering the entire adult life span. The potential
limitations of this approach are fourfold. Firstly, combining samples
from different research domains may have led to increased heterogeneity.
Secondly, in some studies the control samples were not as thoroughly described as the observational treatment samples and this could have reduced the effectiveness of the screening process. Thirdly, the wide age
ranges of many studies limited the number of age groups that could be
used in the meta-analysis and this limited precision of the estimates.
More studies with narrow age ranges are required to enable greater precision in estimates of age effects. Finally, it is possible that preclinical neurodegenerative processes have contributed to the atrophy rates reported
in this study for the older age groups.
Conclusions
To our knowledge this is the rst meta-analysis of hippocampal atrophy, investigated in studies employing a longitudinal design, across the
adult lifespan. Hippocampal volumes remain relatively stable with low
levels of atrophy up to the middle of adulthood from which time
atrophy progressively increases as age increases. The heterogeneity between studies also increases in studies surveying older individuals.
More targeted research is required to understand the factors that drive
this variability. Finally, manual segmentation studies produced higher atrophy estimates compared to automated and semi-automated studies. It
is unclear whether the difference relates to the segmentation technique
or the hippocampal boundaries used. The implication of this nding is
that separate benchmarks may need to be used when assessing ndings
based on differing segmentation approaches.
Acknowledgments
This study was funded by Australian Research Council project grant
number 120101705. The funding sources were not involved in the
design, collection, analysis or interpretation of data; or in the writing
of the report or the decision to submit.
Appendix A. Supplementary data
Supplementary data to this article can be found online at http://dx.
doi.org/10.1016/j.neuroimage.2015.03.035.

Gender

References

Hippocampal atrophy was not separately measured in males and females in any of the studies. Therefore it was not possible to perform any
gender based meta-analyses. However, a number of studies controlled
or tested for gender effects, with one study reporting greater hippocampal
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of the male-only studies, Whitworth et al. (2005), found annualised atrophy of 1.25% per year in young men, which is somewhat higher than the
meta-analysis estimate, but in line with the limited information from the
few studies investigating gender effects in hippocampal atrophy. Signicant negative correlations have been found between hippocampal volume and age in men, but not in women, from around 20 to 46 years of
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that few studies measure hippocampal atrophy separately in each gender.
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