Neuropsychology © 2016 American Psychological Association

2016, Vol. 30, No. 8, 906 –914 0894-4105/16/$12.00 http://dx.doi.org/10.1037/neu0000287

Neuronal Correlates of Serial Position Performance in Amnestic Mild

Cognitive Impairment
Elisabeth Kasper Katharina Brueggen and Michel J. Grothe
University of Rostock German Center for Neurodegenerative Diseases
(DZNE)–Rostock/Greifswald, Rostock, Germany

Davide Bruno Nunzio Pomara

Liverpool Hope University Nathan Kline Institute for Psychiatric Research, Orangeburg,
New York, and New York University
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Elisabeth Unterauer, Marco Duering, Stefan Teipel

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and Michael Ewers University of Rostock and German Center for

Institute for Stroke and Dementia Research (ISD), University Neurodegenerative Diseases (DZNE)–Rostock/Greifswald,
Hospital Munich, Munich, Germany Rostock, Germany

Katharina Buerger
Institute for Stroke and Dementia Research (ISD), University Hospital Munich, Munich, Germany

Objectives: Delayed recall of the first words of a list—the primacy position—is thought to be particularly
dependent on intact memory consolidation. Hippocampal volume has been suggested as the primary
neuronal correlate of delayed primacy recall in cognitively normal elderly individuals. Here, we studied
the association of hippocampal volume with primacy recall in individuals with amnestic mild cognitive
impairment (aMCI). Method: We investigated serial position performance in 88 subjects with aMCI
using a 16-word list (the California Verbal Learning Test [CVLT]). Primacy and recency performance
were measured during learning and delayed recall. Hippocampal volumes were automatically determined
from structural MRI scans. We conducted regression analyses with bilateral hippocampal volumes as
predictors and serial position indices as outcomes. Results: After controlling for age, gender, and total
intracranial volume, bilateral hippocampal volume was not associated with primacy recall either during
learning or delayed recall. Primacy performance during learning was associated with the right inferior
and middle temporal gyrus as well as the right inferior parietal cortex and supramerginal gyrus. During
delayed recall, primacy performance was related to the bilateral supramarginal gyri. Conclusions: Our
findings suggest a reduced primacy effect in aMCI already during learning, contrasting previous findings
in normal cognitive aging. This might indicate impaired encoding and consolidation processes at an early
stage of episodic memory acquisition. Furthermore, our data indicate that hippocampal volume may not
be a relevant determinant of residual primacy performance in the stage of aMCI, which may rather
depend on temporal and parietal neocortical networks.

Keywords: amnestic mild cognitive impairment, primacy, serial position effects, hippocampus, memory,
Alzheimer’s disease

Impaired episodic memory, the main clinical feature of Alzhei- that can be stored in memory (Craik & Lockhart, 1972). Consol-
mer’s disease (AD), reflects reduced encoding and consolidation idation generally refers to the transfer of information from short-
(Carlesimo & Oscar-Berman, 1992). Encoding is the process of term memory (STM) into long-term memory, making it available
perceiving a stimulus and transforming it into a unit of information for later retrieval, including after a delay (McGaugh, 2000). Suc-

This article was published Online First May 16, 2016. Psychosomatic Medicine, University of Rostock, and German Center for
Elisabeth Kasper, Department of Psychosomatic Medicine, University of Neurodegenerative Diseases (DZNE)–Rostock/Greifswald; Katharina
Rostock; Katharina Brueggen and Michel J. Grothe, German Center for Buerger, Institute for Stroke and Dementia Research (ISD), University
Neurodegenerative Diseases (DZNE)–Rostock/Greifswald, Rostock, Ger- Hospital Munich.
many; Davide Bruno, Department of Psychology, Liverpool Hope Univer- The authors have no funding or support to report, and the authors have
sity; Nunzio Pomara, Nathan Kline Institute for Psychiatric Research, declared that no competing interests exist.
Orangeburg, New York, and Department of Psychiatry, School of Medi- Correspondence concerning this article should be addressed to Elisabeth
cine, New York University; Elisabeth Unterauer, Marco Duering, and Kasper, Department of Psychosomatic Medicine, University Hospital
Michael Ewers, Institute for Stroke and Dementia Research (ISD), Uni- Rostock, Gehlsheimer Straße 20, 18147 Rostock, Germany. E-mail:
versity Hospital Munich, Munich, Germany; Stefan Teipel, Department of [email protected]

906
 NEURONAL CORRELATES OF PRIMACY PERFORMANCE IN MCI 907

cessful recall performance, therefore, is considered an indicator of More recently, decreased primacy performance in delayed recall
effective encoding and consolidation processes. has been found to be a sensitive predictor of the conversion from
Serial position effects refer to the observation that words at the MCI to AD (Egli et al., 2014, 2015). However, the neuronal
beginning of a list (primacy words) and words at the end of a list correlates of primacy performance in patients with a manifest
(recency words) are remembered typically better than words in the memory impairment have not been investigated yet.
middle of a list (primacy effect or recency effect, respectively; The present cross-sectional study aimed to examine neuronal
Murdock, 1962). While the recency effect is commonly thought to correlates of primacy performance in a group of 88 individuals
rely mainly on STM (Atkinson & Shiffrin, 1971), the primacy with amnestic MCI (aMCI). More specifically, we investigated
effect is believed to emerge as a consequence of frequent rehearsal whether and to what extent primacy performance in delayed recall
opportunities for early list items, thus leading to the information is associated with MRI-measured hippocampal volume in aMCI.
being stored within long-term memory more effectively (Atkinson Further, we compared this effect to the association of hippocampal
& Shiffrin, 1968). A preserved primacy effect may therefore be a volume with recency performance and total recall performance. In
particularly sensitive indicator for intact memory encoding and addition, unbiased whole-brain analyses were used to explore
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consolidation. which brain structures outside the hippocampus are associated

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Encoding and consolidation processes strongly depend on hip- with primacy performance in aMCI.
pocampal functioning (Wixted, 2004), although the exact role of
the hippocampus in these processes is still a matter of debate. For Method
example, it is not clear to date whether the hippocampus is in-
volved in the consolidation process for only a limited amount of
Participants
time—that is, until the information has been transferred to asso-
ciation cortices (Squire, 1992)— or whether the hippocampus is We included baseline data of 88 individuals with aMCI from a
required to represent and reencode the information each time it is sample recruited for an intervention study conducted by the Uni-
remembered, so that memory contents are combined into a versity Hospital Munich, Munich, Germany. The study received
multiple-trace representation in the brain over the life span (mul- ethical approval from the local Ethics Committee of the Faculty of
tiple trace theory; Nadel & Moscovitch, 1997). Lesion and fMRI Medicine of Ludwig Maximilian University, Munich, Germany.
studies have investigated the association between hippocampal All aMCI patients fulfilled the Petersen criteria (Petersen et al.,
functioning and primacy as an indicator for consolidation pro- 1999):
cesses (e.g., Hermann et al., 1996; Strange, Otten, Josephs, Rugg,
& Dolan, 2002). While these studies confirm a central role of the 1. They described a subjective memory complaint.
hippocampus, the extent of its contribution remains unclear com-
pared to other brain structures such as frontal regions. 2. They showed memory performance of at least a 1.5
In normal cognitive aging, characteristic patterns of serial po- standard deviation below the age- and education-adjusted
sition effects are preserved even when overall recall performance norm assessed by the Consortium to Establish a Registry
is decreased (e.g., Mitrushina, Satz, Chervinsky, & D’Elia, 1991). for Alzheimer’s Disease (CERAD) test battery.
Interestingly, in a group of 204 healthy older people, delayed recall
3. No clinically significant functional impairment of activ-
performance of primacy words predicted subsequent global cog-
ities of daily living or manifest dementia was present.
nitive decline, as measured with the Mini Mental State Examina-
tion, with higher accuracy than overall delayed recall performance 4. Clinical Dementia Rating (CDR) score was 0.5 in all
(Bruno, Reiss, Petkova, Sidtis, & Pomara, 2013). This finding may cases.
indicate that primacy performance is a particularly sensitive indi-
cator of incipient memory decline, possibly because of its high All patients were characterized either as aMCI single domain
reliance on intact hippocampus function. Accordingly, among cog- (with a selective impairment of verbal memory or both verbal and
nitively intact elderly individuals, primacy performance was spe- figural memory; i.e., z score ⬍ ⫺1.5) or aMCI multiple domain
cifically associated with hippocampal volume as measured with (with an impairment of memory as well as other cognitive do-
structural MRI (Bruno et al., 2015). mains; e.g., phonemic fluency; Petersen, 2004; Petersen et al.,
Serial position effects have also been found to discriminate 2001). Our study sample consisted of 34 patients with aMCI single
between healthy cognitive aging, mild cognitive impairment domain and 54 patients with aMCI multiple domain. The groups
(MCI) as a prodromal stage of dementia, and clinically manifest did not differ significantly in verbal episodic memory scores.
dementia in AD (Cunha, Guerreiro, de Mendonca, Oliveira, & Table 1 summarizes the subjects’ demographic and clinical char-
Santana, 2012; Howieson et al., 2011; Moser et al., 2014). More acteristics, including the statistical comparison between the MCI
specifically, the primacy effect was found to be reduced in MCI subgroups as well as the effect sizes. Figure 1 shows the CERAD
patients, and even more so in AD dementia patients, when com- performance.
pared to healthy elderly individuals (Cunha et al., 2012; Howieson
et al., 2011; Moser et al., 2014). In contrast, the recency effect in
Assessment of Verbal Episodic Memory
cohorts of MCI and especially in AD was found to be significantly
increased; that is, relatively more recency words were recalled Verbal episodic memory was assessed in detail using the
compared to primacy and middle words. This could be due to California Verbal Learning Test (CVLT; Delis, Kramer, Ka-
relatively retained STM as compared to long-term consolidation plan, & Ober, 1987). The CVLT is a standardized list-learning
processes (Bäckman, Small, & Fratiglioni, 2001). test and consists of two word lists (A and B) of 16 words each.
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908

Table 1
Demographical and Clinical Data

aMCI single
domain
versus
aMCI
Total sample aMCI single domain aMCI multiple domain multiple
(N ⫽ 88) (N ⫽ 34) (N ⫽ 54) domain
Variables M SD Range M SD Range M SD Range Effect sizea

Demographics
Age (years) 74.1 5.58 61.0 87.0 73.3 5.98 61.0 85.0 74.6 5.31 65.0 87.0 .23
Gender (N male or
female) 44/44 12/22 32/22 .23
Educationb
(1/2/3/4/5) 0/24/23/19/22 0/14/6/7/7 0/10/17/12/15 .26

Cognitive performance (CERAD)

MMSE 27.3 1.69 22.0 30.0 27.9 1.58 24.0 30.0 26.8 1.63 22.0 30.0 ⫺.68ⴱⴱ
Word list learning ⫺1.9 .96 ⫺4.2 .6 ⫺1.8 .89 ⫺4.0 .6 ⫺2.0 1.01 ⫺4.2 .2 ⫺.21
Word list recall ⫺1.5 .92 ⫺4.2 .3 ⫺1.4 .81 ⫺2.9 .3 ⫺1.6 .97 ⫺4.2 .0 ⫺.22
KASPER ET AL.

Word list recognition ⫺1.5 1.37 ⫺5.3 .9 ⫺1.5 1.64 ⫺5.3 .9 ⫺1.5 1.18 ⫺5.0 .7 .00
Constructional praxis
recall ⫺1.0 1.46 ⫺3.4 2.5 ⫺.3 1.59 ⫺3.0 2.5 ⫺1.4 1.21 ⫺3.4 1.3 ⫺.80ⴱⴱⴱ
Trail Making Test—
Part A ⫺.5 1.03 ⫺3.2 1.9 .0 .96 ⫺1.8 1.9 ⫺.8 .95 ⫺3.2 1.7 ⫺.84ⴱⴱⴱ
Trail Making Test—
Part B ⫺.5 1.13 ⫺2.5 2.9 .0 .99 ⫺2.4 1.5 ⫺1.0 1.06 ⫺2.5 2.9 ⫺.97ⴱⴱⴱ
Phonemic fluency .2 1.22 ⫺3.4 2.8 .8 1.17 ⫺2.6 2.8 ⫺.2 1.09 ⫺3.4 2.0 ⫺.89ⴱⴱⴱ
Constructional praxis .1 1.19 ⫺2.5 1.7 .4 1.13 ⫺2.4 1.7 ⫺.1 1.20 ⫺2.5 1.6 ⫺.43ⴱ
Semantic fluency ⫺.8 1.10 ⫺3.7 2.5 ⫺.1 .87 ⫺1.4 2.5 ⫺1.2 1.02 ⫺3.7 .9 ⫺1.14ⴱⴱⴱ
Boston Naming Test ⫺.3 1.27 ⫺3.6 1.6 .3 .93 ⫺1.4 1.6 ⫺.7 1.32 ⫺3.6 1.6 ⫺.84ⴱⴱⴱ
Note. N ⫽ Number of subjects; aMCI ⫽ amnestic mild cognitive impairment; SD ⫽ standard deviation; CERAD ⫽ Consortium to Establish a Registry for Alzheimer’s Disease; MMSE ⫽ Mini Mental
State Examination.
a
Cohen’s d (Cohen’s w for gender and education). b The subjects’ education levels were converted to a categorical scale based on the German education system, ranging from 1 (i.e., no educational
qualification) to 5 (i.e., university degree).
ⴱ
p ⬍ .05. ⴱⴱ p ⬍ .01. ⴱⴱⴱ p ⬍ .001.
 NEURONAL CORRELATES OF PRIMACY PERFORMANCE IN MCI 909

gray-matter maps, and voxel values were modulated to account for the
volumetric differences introduced by the high-dimensional warps,
such that the total amount of gray-matter volume present before
warping was preserved. The total intracranial volume (TIV) was
calculated as the sum of the total segmented gray-matter, white-
matter, and cerebrospinal fluid volumes in native space. For the
voxel-wise whole-brain analyses, warped gray-matter maps were
smoothed with a Gaussian smoothing kernel of 8 mm full width at
half maximum.
For the region of interest (ROI) analyses, individual gray-matter
volumes of the left and right hippocampus were automatically
extracted from the warped gray-matter segments by summing up
the modulated voxel values using a predefined hippocampus mask
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in template space (before smoothing). This mask was obtained by

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manual delineation of the hippocampus in the MNI standard space

template used for spatial normalization. Tracing of the hippocam-
Figure 1. Cognitive performance of CERAD subtests. pus outlines followed recently developed international consensus
criteria for manual hippocampus segmentation on MRI (Boccardi
et al., 2015); http://www.hippocampal-protocol.net/SOPs/index
The words belong to four semantic categories but are presented
in a pseudorandom order. First, List A is presented orally to the .php) and was performed by a certified tracer using MultiTracer 1.0
subject in five learning trials. After each trial, the subject is software (http://www.loni.usc.edu/Software/MultiTracer).
asked to freely recall the words. After that, a distractor List B This approach extends previously validated automated volume-
is presented, and subjects are asked to recall the items from List try approaches within SPM software by incorporating high-
B. Subsequently, subjects are requested to recall the items from dimensional image normalization (Firbank, Barber, Burton, &
List A (immediate recall). After a delay of 20 min, subjects O’Brien, 2008), which has been shown to further increase the
perform a delayed recall (DR) test and a recognition trial. performance of such automated volumetry approaches (Klein et
We assessed the total recall scores by the proportion of al., 2009).
correctly recalled words from all words (maximum of 16) for
the learning phase and DR. In accordance with previously
published studies (Bruno et al., 2013; Egli et al., 2014), primacy Statistical Analysis
performance was defined as the proportion of the number of
correctly recalled items from the first four items of a word list. Behavioral data. Serial position effects were compared both
Recency performance was defined as the proportion of the within and across the recall phases (learning phase and DR). Due
number of correctly recalled items from the last four items. to nonnormally distributed test variables, Wilcoxon tests for
Finally, middle performance was defined as the proportion of between-group comparisons were used. The significance level was
correctly recalled items from the eight middle positions be- set to p ⬍ .05.
tween the primacy and recency words. As many subjects scored zero in the recall phase, we tested for
a possible floor effect by performing a secondary analysis after the
MRI exclusion of subjects with a score of zero in DR. Thus, 66 indi-
viduals were included in this analysis.
MRI acquisition. MRI data were acquired with a single 3T MRI data. For the ROI-based analysis, we performed sepa-
Siemens Magnetom Verio Scanner (Siemens, Erlangen, Germany; rate multiple linear regression analyses of left and right hippocam-
Syngo MR B17) in Munich, Germany, using a 12-channel head coil. pal gray-matter volume on total recall, primacy, and recency
T1-weighted, high-resolution structural MRI volumes of the brain
performance for the learning phase and DR separately. The control
were scanned using a 3-D magnetization-prepared rapid gradient echo
variables were age, gender, education, TIV, and aMCI subtype.
sequence (echo time [TE] ⫽ 3.06 ms, repetition time [TR] ⫽ 2,100
Due to normally distributed residuals, we decided to use regression
ms, inversion time [TI] ⫽ 900 ms, bandwidth ⫽ 230 Hz per pixel,
models despite partial variable skewness.
matrix ⫽ 240 ⫻ 256 ⫻ 160, isometric voxel size ⫽ 1.0 mm3).
MRI processing. Processing of T1 MPRAGE images was con- For the complementary whole-brain analyses, total recall, pri-
ducted by using established methods of voxel-wise morphometry macy, and recency performance were used as predictor variables in
(VBM; Ashburner, 2009). T1 MPRAGE images were segmented into separate voxel-wise regression models controlling for the covari-
gray matter, white matter, and cerebrospinal fluid and high- ates age, gender, education, TIV, and aMCI subtype. With a
dimensionally registered to Montreal Neurological Institute (MNI) minimal cluster size of 50 voxels, the statistical threshold was set
standard space using a segmentation routine without reliance on tissue to p ⬍ .001, uncorrected for multiple comparisons.
priors and the diffeomorphic diffeomorphic anatomical registration To account for floor effects, we reanalyzed the MRI data in
through exponentiated lie (DARTEL) warping algorithm (Ashburner, the same way as the behavioral data (excluding individuals who
2007), implemented in the VBM8 toolbox in Statistical Parametric scored zero in DR, 66 individuals were included in the reanal-
Mapping (SPM) 8. Warping parameters were applied to individual ysis).
 910 KASPER ET AL.

Results Whole-brain analyses. Table 2 reports the peak-level coor-

dinates and cluster sizes of the whole-brain voxel-based regression
analyses.
Behavioral Data
Primacy performance. Primacy in the learning phase showed
The CVLT total recall and serial position performances are significant associations with gray-matter volume in the left inferior
presented in Figure 2. Within the learning phase (CVLT Trials parietal lobe, the left supramarginal gyrus, and the right middle
1–5), recency performance was significantly higher than primacy and inferior temporal gyrus (Figure 3). DR primacy performance
performance, z(N ⫽ 88) ⫽ ⫺6.675, p ⬍ .001, as well as signifi- was only significantly associated with gray-matter volume in the
cantly higher than middle performance, z(N ⫽ 88) ⫽ ⫺7.881, p ⬍ bilateral supramarginal gyrus (Figure 3).
.001. Primacy performance was significantly higher than middle Recency performance. Recency in the learning phase showed
performance, z(N ⫽ 88) ⫽ ⫺3.815, p ⬍ .001. significant associations with gray-matter volume in the left middle
For DR, primacy performance revealed the highest value and and inferior temporal gyrus as well as in the left occipital and
was significantly different from recency performance, z(N ⫽ frontal pole (Figure 4). DR recency performance was associated
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88) ⫽ ⫺3.926, p ⬍ .001, but not from middle performance, z(N ⫽ with the right supramarginal gyrus, right frontal orbital cortex,
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88) ⫽ ⫺1.666, p ⫽ .096. Recency performance was significantly amygdala bilaterally, and cerebellar cortex (Figure 4).
lower than middle performance, z(N ⫽ 88) ⫽ ⫺2.672, p ⫽ .008. Total recall performance. Total recall performance in the
Comparing serial position effects across the different recall learning phase showed significant associations with bilateral clus-
phases, recency performance was significantly lower in DR com- ters of gray-matter volume in the superior and middle temporal
pared to the learning phase, z(N ⫽ 88) ⫽ ⫺7.719, p ⬍ .001. There gyrus, the cerebellar cortex, and the amygdala, as well as in the left
were no differences between the learning phase and DR for both hippocampus and parahippocampal gyrus (see Figure 5). In addi-
primacy performance, z(N ⫽ 88) ⫽ ⫺1.218, p ⫽ .223, and middle tion, smaller clusters were found in the left supramarginal gyrus
performance, z(N ⫽ 88) ⫽ ⫺.066, p ⫽ .947. and right cingulate cortex as well as the orbital frontal cortex. Total
DR performance was associated with the volume of the bilateral
MRI Data supramarginal gyrus, the left angular gyrus, and the left amygdala
(Figure 5).
ROI analyses. Overall, the results did not change after the exclusion of subjects
Serial position performance. We found no significant associ- with a score of zero in DR.
ations between hippocampal volumes and primacy or recency
performance, respectively, neither in the learning phase nor in DR.
Discussion
Excluding subjects with a score of zero in DR did not change the
results. Our study investigated associations between serial position ef-
Total recall performance. Both left and right hippocampal fects, particularly primacy performance in a verbal memory task
volumes were significant predictors of total recall performance in and hippocampus gray-matter volume in a group of aMCI subjects.
the learning phase. The regression model including the main The behavioral data showed a primacy effect during the learning
predictor of left hippocampal volume (p ⫽ .002, ␤ ⫽ 0.322, partial phase that was much lower than the recency effect. During DR, no
R ⫽ 0.332) and all control variables explained approximately 40% primacy effect was observed. In addition, hippocampal volume
of the variance (R2 ⫽ 0.404, F ⫽ 10.82, p ⬍ .0001). was not significantly associated with the primacy performance,
The model including the main predictor of right hippocampal neither during learning nor DR. A whole-brain analysis revealed
volume (p ⫽ .012, ␤ ⫽ 0.259, partial R ⫽ 0.274) explained 38% parietotemporal structures to be involved in the remaining primacy
of the variance (R2 ⫽ 0.380, F ⫽ 9.90, p ⬍ .0001). performance in aMCI.
In the regression models of DR (R2 ⫽ 0.393, F ⫽ 10.40, p ⬍ We found that primacy recall during the learning phase was
.0001), only the left hippocampal volume, but not the right vol- significantly better than recall of words in the middle of the list.
ume, was a significant predictor (␤ ⫽ 0.268, p ⫽ .011, partial R ⫽ However, the primacy effect was significantly lower than the
0.278). recency effect. This is in contrast to the performance of healthy

Figure 2. CVLT total recall and serial position performances within each recall phase.
 NEURONAL CORRELATES OF PRIMACY PERFORMANCE IN MCI 911

Table 2
Results From Whole-Brain Linear Regression Models Including All Control Variables

MNI coordinates
Serial position
performance Cortical area Cluster size Peak t values x y z

Primacy
Learning L Inferior parietal lobe 603 4.18 ⫺48 ⫺49 43
R Middle temporal gyrus 148 3.73 69 ⫺39 ⫺15
R Inferior temporal gyrus 58 3.72 54 ⫺48 ⫺11
L Supramarginal gyrus 77 3.65 ⫺48 ⫺22 30
DR L Supramarginal gyrus 76 3.75 ⫺45 ⫺24 31
R Supramarginal gyrus 96 3.62 58 ⫺12 22
Recency
Learning R Occipital pole 60 4.51 20 ⫺91 10
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L Inferior temporal gyrus 516 4.79 ⫺51 ⫺25 ⫺18

⫺36
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L Frontal pole 69 3.92 41 10

L Inferior temporal gyrus 447 4.20 ⫺48 ⫺3 ⫺45
DR R Supramarginal gyrus 270 3.79 60 ⫺12 27
R Cerebellum 137 3.90 12 ⫺46 ⫺53
L Cerebellum 106 3.56 ⫺10 ⫺48 ⫺50
R Amygdala 111 3.54 26 4 ⫺17
L Amygdala 118 3.55 ⫺16 2 ⫺15
Total recall
Learning L Middle temporal gyrus 1,045 5.00 ⫺56 ⫺28 ⫺14
L Amygdala parahippocampal gyrus 1,245 4.51 ⫺30 ⫺3 ⫺15
R Cingulate gyrus 517 4.38 10 ⫺42 3
L Hippocampus 196 4.11 ⫺28 ⫺34 4
L Supramarginal gyrus 252 3.71 ⫺46 ⫺45 43
R Cerebellum 58 3.75 15 ⫺48 ⫺50
L Middle temporal gyrus 270 3.64 ⫺46 ⫺4 ⫺27
R Frontal orbital cortex 260 3.66 21 9 ⫺11
R Inferior temporal gyrus 118 3.85 51 ⫺22 ⫺23
DR L Supramarginal gyrus, angular gyrus 195 3.80 ⫺54 ⫺58 48
L Amygdala 165 3.73 ⫺15 0 ⫺14
R Supramarginal gyrus 473 3.78 69 ⫺4 21
Note. MNI ⫽ Montreal Neurological Institute; DR ⫽ delayed recall; L ⫽ left; R ⫽ right.

individuals who show no difference between primacy and recency However, the difference between primacy and recency effects
effects during learning on similar tasks (Mitrushina et al., 1991) during the learning phase seemed to be higher in the present study
but confirms previous findings in individuals with MCI (Cunha et than in previous studies (e.g., Cunha et al., 2012). The perfor-
al., 2012; Howieson et al., 2011; Martín et al., 2013). mance of our aMCI subjects appeared similar to that of patients

Figure 3. Whole-brain regression analyses—primacy performance as predictor. Voxel-based analyses of the associations
between primacy performance and regional gray-matter volumes in the learning phase and delayed recall. Effects of primacy
performance on regional gray-matter volume are shown on coronal sections through the Montreal Neurological Institute
(MNI) space template. With a minimal cluster size of 50 voxels, the statistical threshold was set to p ⬍ .001, uncorrected
for multiple comparisons. See the online article for the color version of this figure.
 912 KASPER ET AL.
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Figure 4. Whole-brain regression analyses—recency performance as predictor. Voxel-based analyses of the associations
between recency performance and regional gray-matter volumes in the learning phase and delayed recall. Effects of recency
performance on regional gray-matter volume are shown on coronal sections through the Montreal Neurological Institute
(MNI) space template. With a minimal cluster size of 50 voxels, the statistical threshold was set to p ⬍ .001, uncorrected
for multiple comparisons. See the online article for the color version of this figure.

with manifest AD who typically present a notable recency effect cesses are already affected at an early stage of information acqui-
(Cunha et al., 2012; Foldi, Brickman, Schaefer, & Knutelska, sition in amnestic MCI.
2003; Howieson et al., 2011; Martín et al., 2013). The difference With regard to DR, our study data showed no primacy effect.
between our study and previous MCI studies may be related to the This finding is in contrast to the findings of Martín et al. (2013),
different selection criteria of the samples. We investigated only the only previous publication that also investigated serial position
aMCI subjects, while in other studies both amnestic and nonam- effects in DR in MCI patients. However, compared to Martín et
nestic MCI subjects were included or the primary domain of al.’s (2013) sample, our data showed a less pronounced primacy
cognitive impairment was not further specified (Egli et al., 2014). effect during the learning phase, possibly reflecting a disturbed
This may lead to pronounced differences in serial position effects. early consolidation process followed by a less successful transfer
For example, Moser et al. (2014) showed that patients with am- of information into long-term storage. The strongly reduced re-
nestic MCI— but not individuals with nonamnestic MCI— exhib- cency effect during DR in our sample appears to be consistent with
ited a pattern of a relatively small primacy effect compared to a the findings of Martín et al. (2013).
notable recency effect, whereas individuals with nonamnestic MCI Future longitudinal studies will have to investigate the use of serial
presented with a profile similar to that of older healthy persons position effects compared to established memory indices for the
with no difference between primacy and recency effect. A reduced prediction of cognitive decline and conversion to dementia. While
primacy effect compared to a much more pronounced recency there are numerous studies suggesting serial position effects to be
effect during learning implies that encoding and rehearsal pro- more sensitive than global recall in measuring episodic memory and

Figure 5. Whole-brain regression analyses—total recall performance as predictor. Voxel-based analyses of the associ-
ations between recall performance and regional gray-matter volumes in the learning phase and delayed recall. Effects of total
recall performance on regional gray-matter volume are shown on coronal sections through the Montreal Neurological
Institute (MNI) space template. With a minimal cluster size of 50 voxels, the statistical threshold was set to p ⬍ .001,
uncorrected for multiple comparisons. See the online article for the color version of this figure.
 NEURONAL CORRELATES OF PRIMACY PERFORMANCE IN MCI 913

predicting cognitive decline (Bruno et al., 2013; Egli et al., 2014, characteristics. Although diagnosis of MCI used well-established
2015), other studies comparing the sensitivity and specificity of mem- criteria (Petersen et al., 1999), biomarker-supported diagnosis
ory indices did not find evidence for a high discriminability between could not be provided in all cases.
different indices (Boone, Lu, & Wen, 2005). Another methodological aspect that has to be discussed is the
In contrast to findings reported for cognitively intact older liberal statistical threshold in the voxel-based analyses. Our ROI
people (Bruno et al., 2015), primacy performance in our MCI approach was hypothesis driven; we expected to find an associa-
sample was not associated with hippocampal volume during learn- tion between hippocampal volume and primacy performance in
ing or DR. This finding was replicated in both the ROI and the our MCI cohort. However, effects were not significant. Because
voxel-based whole-brain analysis. Hippocampal atrophy is usually we did not use multiple comparison correction, the probability of
considered an early sign of AD (Jack et al., 2000), possibly a Type II error (i.e., rejecting an effect although it is present) was
resulting in decreased consolidation, which is reflected by a dis- low. The low Type II error probability suggests a robust lack of
appearing primacy effect. The reduced primacy effect and the lack association between primacy performance and hippocampus vol-
of association of primacy performance with hippocampal volume ume. Additionally, we were interested in identifying potential
This article is intended solely for the personal use of the individual user and is not to be disseminated broadly.

may suggest that the contribution of the hippocampus to memory alternative neuronal networks. For this purpose, we used an ex-
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consolidation declines in the disease progression of AD and that ploratory whole-brain analysis. Due to a low probability for false
other neuronal networks become more relevant for consolidation negative results (statistical Type II errors), these voxel-based find-
and potentially compensate for the loss of hippocampus function ings confirmed the absence of an effect in the hippocampus.
with disease progression. In summary, our findings suggest that individuals with aMCI
Consistent with this argumentation, in the whole-brain voxel-based already show a reduced primacy effect during the learning phase of
analysis, we found inferior parietal structures such as the supramar- episodic memory tests. This differs from previous findings in
ginal gyrus and the inferior parietal cortex, associated with the pri- normal cognitive aging and probably indicates impaired encoding
macy performance during both learning and DR. In general, these and consolidation processes at an early stage of episodic memory
areas are involved in encoding of information and reflect the phono- acquisition. As a consequence, hippocampal volume seems to be a
logical buffer in STM (Paulesu, Frith, & Frackowiak, 1993). An fMRI less relevant determinant of the residual primacy effect in aMCI;
study by Sommer, Rose, and Büchel (2006) investigated neuronal the remaining primacy performance in MCI depends rather on the
correlates of the primacy effect in healthy individuals: For the pri- integrity of temporal and parietal neocortical networks.
macy performance, an involvement of the inferior parietal gyrus and
angular gyrus was found. The authors argued that, due to their initial
position, primacy words need a particularly efficient encoding. As we References
found inferior parietal rather than hippocampal involvement, we
Ashburner, J. (2007). A fast diffeomorphic image registration algorithm.
would assume that encoding is preserved in MCI and that the primacy
NeuroImage, 38, 95–113. http://dx.doi.org/10.1016/j.neuroimage.2007
effect involves a higher proportion of STM processes in MCI patients .07.007
than in healthy older people. Ashburner, J. (2009). Computational anatomy with the SPM software.
Further structures associated with primacy performance during Magnetic Resonance Imaging, 27, 1163–1174. http://dx.doi.org/10
learning were the right middle and inferior temporal gyrus. These .1016/j.mri.2009.01.006
areas are involved in perceiving (Cabeza & Nyberg, 2000) and rec- Atkinson, R. C., & Shiffrin, R. M. (1968). Human memory: A proposed
ognizing objects (Chao, Haxby, & Martin, 1999). As perceiving a system and its control processes. Psychology of Learning and Motiva-
stimulus is a first step in the process of encoding, these findings tion, 2, 89 –195. http://dx.doi.org/10.1016/S0079-7421(08)60422-3
confirm the importance of the encoding phase for learning in MCI Atkinson, R. C., & Shiffrin, R. M. (1971). The control processes of short-term
patients. memory. Stanford, CA: Stanford University.
Bäckman, L., Small, B. J., & Fratiglioni, L. (2001). Stability of the preclinical
Our whole-brain analysis showed only a weak relationship between
episodic memory deficit in Alzheimer’s disease. Brain: A Journal of Neu-
total recall and hippocampal gray-matter volume in the learning
rology, 124, 96 –102. http://dx.doi.org/10.1093/brain/124.1.96
phase. In contrast, we observed a strong association with the Boccardi, M., Bocchetta, M., Ganzola, R., Robitaille, N., Redolfi, A.,
amygdala. One may assume that the consolidation function driven by Duchesne, C. R., . . . Frisoni, G. B. (2015). Operationalizing protocol
the medial limbic circuit (Shah, Jhawar, & Goel, 2012) in normal differences for EADC-ADNI manual hippocampal segmentation. Alz-
individuals is increasingly taken over by basolateral limbic structures heimer’s & Dementia, 11, 184 –194. http://dx.doi.org/10.1016/j.jalz
in the course of disease progression of AD (Sarter & Markowitsch, .2013.05.801
1985). However, a single fMRI study showed rather frontal compen- Boone, K. B., Lu, P., & Wen, J. (2005). Comparison of various RAVLT
satory activity within the medial limbic circuit (Browndyke et al., scores in the detection of noncredible memory performance. Archives of
2013). Further research is needed to resolve this question. Clinical Neuropsychology, 20, 301–319. http://dx.doi.org/10.1016/j.acn
As expected, with regard to the recency performance, no asso- .2004.08.001
ciations with the hippocampus were observed. This is in line with Browndyke, J. N., Giovanello, K., Petrella, J., Hayden, K., Chiba-Falek,
O., Tucker, K. A., . . . Welsh-Bohmer, K. A. (2013). Phenotypic regional
the suggested reliance of recency performance on STM processes
functional imaging patterns during memory encoding in mild cognitive
independent of hippocampal function (Davelaar, Goshen- impairment and Alzheimer’s disease. Alzheimer’s & Dementia: The
Gottstein, Ashkenazi, Haarmann, & Usher, 2005). Journal of the Alzheimer’s Association, 9, 284 –294. http://dx.doi.org/
One major limitation of our study is the small variance with 10.1016/j.jalz.2011.12.006
regard to serial position performance and considerable floor ef- Bruno, D., Grothe, M. J., Nierenberg, J., Zetterberg, H., Blennow, K.,
fects. We attempted to minimize this confound by excluding zero Teipel, S. J., & Pomara, N. (2015). A study on the specificity of the
results in the behavioral data. A further limitation is the sample association between hippocampal volume and delayed primacy perfor-
 914 KASPER ET AL.

mance in cognitively intact elderly individuals. Neuropsychologia, 69, algorithms applied to human brain MRI registration. NeuroImage, 46,
1– 8. http://dx.doi.org/10.1016/j.neuropsychologia.2015.01.025 786 – 802. http://dx.doi.org/10.1016/j.neuroimage.2008.12.037
Bruno, D., Reiss, P. T., Petkova, E., Sidtis, J. J., & Pomara, N. (2013). Martín, M. E., Sasson, Y., Crivelli, L., Roldán Gerschovich, E., Campos,
Decreased recall of primacy words predicts cognitive decline. Archives of J. A., Calcagno, M. L., . . . Allegri, R. F. (2013). Relevancia del efecto
Clinical Neuropsychology, 28, 95–103. http://dx.doi.org/10.1093/arclin/ de posición serial en el diagnóstico diferencial entre el deterioro cogni-
acs116 tivo leve, la demencia de tipo Alzheimer, y el envejecimiento normal
Cabeza, R., & Nyberg, L. (2000). Imaging cognition II: An empirical [Relevance of the serial position effect in the differential diagnosis of
review of 275 PET and fMRI studies. Journal of Cognitive Neurosci- mild cognitive impairment, Alzheimer-type dementia, and normal age-
ence, 12, 1– 47. http://dx.doi.org/10.1162/08989290051137585 ing]. Neurología (Barcelona, Spain), 28, 219 –225. http://dx.doi.org/10
Carlesimo, G. A., & Oscar-Berman, M. (1992). Memory deficits in Alz- .1016/j.nrl.2012.04.013
heimer’s patients: A comprehensive review. Neuropsychology Review, McGaugh, J. L. (2000). Memory—A century of consolidation. Science,
3, 119 –169. http://dx.doi.org/10.1007/BF01108841 287, 248 –251. http://dx.doi.org/10.1126/science.287.5451.248
Chao, L. L., Haxby, J. V., & Martin, A. (1999). Attribute-based neural Mitrushina, M., Satz, P., Chervinsky, A., & D’Elia, L. (1991). Performance
substrates in temporal cortex for perceiving and knowing about objects. of four age groups of normal elderly on the Rey Auditory-Verbal
This article is intended solely for the personal use of the individual user and is not to be disseminated broadly.

Nature Neuroscience, 2, 913–919. http://dx.doi.org/10.1038/13217 Learning Test. Journal of Clinical Psychology, 47, 351–357.
Moser, B., Deisenhammer, E. A., Marksteiner, J., Papousek, I., Fink, A., &
This document is copyrighted by the American Psychological Association or one of its allied publishers.

Craik, F. I., & Lockhart, R. S. (1972). Levels of processing: A framework

for memory research. Journal of Verbal Learning and Verbal Behavior, Weiss, E. M. (2014). Serial position effects in patients with mild cog-
11, 671– 684. http://dx.doi.org/10.1016/S0022-5371(72)80001-X nitive impairment and early and moderate Alzheimer’s disease com-
Cunha, C., Guerreiro, M., de Mendonça, A., Oliveira, P. E., & Santana, I. pared with healthy comparison subjects. Dementia and Geriatric Cog-
(2012). Serial position effects in Alzheimer’s disease, mild cognitive nitive Disorders, 37, 19 –26. http://dx.doi.org/10.1159/000351675
impairment, and normal aging: Predictive value for conversion to de- Murdock, B. B., Jr. (1962). The serial position effect of free recall. Journal
mentia. Journal of Clinical and Experimental Neuropsychology, 34, of Experimental Psychology, 64, 482– 488. http://dx.doi.org/10.1037/
841– 852. http://dx.doi.org/10.1080/13803395.2012.689814 h0045106
Davelaar, E. J., Goshen-Gottstein, Y., Ashkenazi, A., Haarmann, H. J., & Nadel, L., & Moscovitch, M. (1997). Memory consolidation, retrograde
amnesia and the hippocampal complex. Current Opinion in Neurobiol-
Usher, M. (2005). The demise of short-term memory revisited: Empir-
ogy, 7, 217–227. http://dx.doi.org/10.1016/S0959-4388(97)80010-4
ical and computational investigations of recency effects. Psychological
Paulesu, E., Frith, C. D., & Frackowiak, R. S. (1993). The neural correlates
Review, 112, 3– 42. http://dx.doi.org/10.1037/0033-295X.112.1.3
of the verbal component of working memory. Nature, 362, 342–345.
Delis, D. C., Kramer, J. H., Kaplan, E., & Ober, B. A. (1987). California
http://dx.doi.org/10.1038/362342a0
Verbal Learning Test: Adult Version. New York, NY: Psychological
Petersen, R. C. (2004). Mild cognitive impairment as a diagnostic entity.
Corporation.
Journal of Internal Medicine, 256, 183–194. http://dx.doi.org/10.1111/
Egli, S. C., Beck, I. R., Berres, M., Foldi, N. S., Monsch, A. U., &
j.1365-2796.2004.01388.x
Sollberger, M. (2014). Serial position effects are sensitive predictors of
Petersen, R. C., Doody, R., Kurz, A., Mohs, R. C., Morris, J. C., Rabins,
conversion from MCI to Alzheimer’s disease dementia. Alzheimer’s &
P. V., . . . Winblad, B. (2001). Current concepts in mild cognitive
Dementia: The Journal of the Alzheimer’s Association, 10(Suppl. 5),
impairment. Archives of Neurology, 58, 1985–1992. http://dx.doi.org/10
S420 –S424. http://dx.doi.org/10.1016/j.jalz.2013.09.012
.1001/archneur.58.12.1985
Egli, S. C., Hirni, D. I., Taylor, K. I., Berres, M., Regeniter, A., Gass, A.,
Petersen, R. C., Smith, G. E., Waring, S. C., Ivnik, R. J., Tangalos, E. G.,
. . . Sollberger, M. (2015). Varying strength of cognitive markers and & Kokmen, E. (1999). Mild cognitive impairment: Clinical character-
biomarkers to predict conversion and cognitive decline in an early-stage- ization and outcome. Archives of Neurology, 56, 303–308. http://dx.doi
enriched mild cognitive impairment sample. Journal of Alzheimer’s .org/10.1001/archneur.56.3.303
Disease, 44, 625– 633. http://dx.doi.org/10.3233/JAD-141716 Sarter, M., & Markowitsch, H. J. (1985). Involvement of the amygdala in
Firbank, M. J., Barber, R., Burton, E. J., & O’Brien, J. T. (2008). Valida- learning and memory: A critical review, with emphasis on anatomical
tion of a fully automated hippocampal segmentation method on patients relations. Behavioral Neuroscience, 99, 342–380. http://dx.doi.org/10
with dementia. Human Brain Mapping, 29, 1442–1449. http://dx.doi .1037/0735-7044.99.2.342
.org/10.1002/hbm.20480 Shah, A., Jhawar, S. S., & Goel, A. (2012). Analysis of the anatomy of the
Foldi, N. S., Brickman, A. M., Schaefer, L. A., & Knutelska, M. E. (2003). Papez circuit and adjoining limbic system by fiber dissection techniques.
Distinct serial position profiles and neuropsychological measures differ- Journal of Clinical Neuroscience, 19, 289 –298. http://dx.doi.org/10
entiate late life depression from normal aging and Alzheimer’s disease. .1016/j.jocn.2011.04.039
Psychiatry Research, 120, 71– 84. http://dx.doi.org/10.1016/S0165- Sommer, T., Rose, M., & Büchel, C. (2006). Dissociable parietal systems
1781(03)00163-X for primacy and subsequent memory effects. Neurobiology of Learning
Hermann, B. P., Seidenberg, M., Wyler, A., Davies, K., Christeson, J., and Memory, 85, 243–251. http://dx.doi.org/10.1016/j.nlm.2005.11.002
Moran, M., & Stroup, E. (1996). The effects of human hippocampal Squire, L. (1992). Declarative and nondeclarative memory: Multiple brain
resection on the serial position curve. Cortex, 32, 323–334. http://dx.doi systems supporting learning and memory. Journal of Cognitive Neuro-
.org/10.1016/S0010-9452(96)80054-2 science, 4, 232–243. http://dx.doi.org/10.1162/jocn.1992.4.3.232
Howieson, D. B., Mattek, N., Seeyle, A. M., Dodge, H. H., Wasserman, D., Strange, B. A., Otten, L. J., Josephs, O., Rugg, M. D., & Dolan, R. J. (2002).
Zitzelberger, T., & Jeffrey, K. (2011). Serial position effects in mild Dissociable human perirhinal, hippocampal, and parahippocampal roles
cognitive impairment. Journal of Clinical and Experimental Neuropsy- during verbal encoding. The Journal of Neuroscience, 22, 523–528.
chology, 33, 292–299. http://dx.doi.org/10.1080/13803395.2010.516742 Wixted, J. T. (2004). The psychology and neuroscience of forgetting.
Jack, C. R., Jr., Petersen, R. C., Xu, Y., O’Brien, P. C., Smith, G. E., Ivnik, Annual Review of Psychology, 55, 235–269. http://dx.doi.org/10.1146/
R. J., . . . Kokmen, E. (2000). Rates of hippocampal atrophy correlate annurev.psych.55.090902.141555
with change in clinical status in aging and AD. Neurology, 55, 484 – 490.
http://dx.doi.org/10.1212/WNL.55.4.484 Received June 24, 2015
Klein, A., Andersson, J., Ardekani, B. A., Ashburner, J., Avants, B., Chiang, Revision received February 25, 2016
M.-C., . . . Parsey, R. V. (2009). Evaluation of 14 nonlinear deformation Accepted February 28, 2016 䡲