Temporal order memory assessed during spatiotemporal navigation as a behavioral cognitive marker for differential Alzheimer's disease diagnosis.
ABSTRACT Episodic memory impairment is a hallmark for early diagnosis of Alzheimer's disease. Most actual tests used to diagnose Alzheimer's disease do not assess the spatiotemporal properties of episodic memory and lead to false-positive or -negative diagnosis. We used a newly developed, nonverbal navigation test for Human, based on the objective experimental testing of a spatiotemporal experience, to differentially Alzheimer's disease at the mild stage (N = 16 patients) from frontotemporal lobar degeneration (N = 11 patients) and normal aging (N = 24 subjects). Comparing navigation parameters and standard neuropsychological tests, temporal order memory appeared to have the highest predictive power for mild Alzheimer's disease diagnosis versus frontotemporal lobar degeneration and normal aging. This test was also nonredundant with classical neuropsychological tests. As a conclusion, our results suggest that temporal order memory tested in a spatial navigation task may provide a selective behavioral marker of Alzheimer's disease.
- SourceAvailable from: Giuseppe Riva[Show abstract] [Hide abstract]
ABSTRACT: A great effort has been made to identify crucial cognitive markers that can be used to characterize the cognitive profile of Alzheimer's disease (AD). Because topographical disorientation is one of the earliest clinical manifestation of AD, an increasing number of studies have investigated the spatial deficits in this clinical population. In this systematic review, we specifically focused on experimental studies investigating allocentric and egocentric deficits to understand which spatial cognitive processes are differentially impaired in the different stages of the disease. First, our results highlighted that spatial deficits appear in the earliest stages of the disease. Second, a need for a more ecological assessment of spatial functions will be presented. Third, our analysis suggested that a prevalence of allocentric impairment exists. Specifically, two selected studies underlined that a more specific impairment is found in the translation between the egocentric and allocentric representations. In this perspective, the implications for future research and neurorehabilitative interventions will be discussed.Ageing Research Reviews 06/2014; 16:32-44. · 7.63 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: The aim of this review is to summarize research on the emerging role of episodic memories in the context of anxiety disorders (AD). The available literature on explicit, autobiographical, and episodic memory function in AD including neuroimaging studies is critically discussed. We describe the methodological diversity of episodic memory research in AD and discuss the need for novel tests to measure episodic memory in a clinical setting. We argue that alterations in episodic memory functions might contribute to the etiology of AD. We further explain why future research on the interplay between episodic memory function and emotional disorders as well as its neuroanatomical foundations offers the promise to increase the effectiveness of modern psychological treatments. We conclude that one major task is to develop methods and training programs that might help patients suffering from AD to better understand, interpret, and possibly actively use their episodic memories in a way that would support therapeutic interventions and counteract the occurrence of symptoms.Frontiers in Behavioral Neuroscience 01/2014; 8:131. · 4.16 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: The validity of neuropsychological tests for the differential diagnosis of degenerative dementias may depend on the clinical context. We constructed a series of logistic models taking into account this factor.American Journal of Alzheimer s Disease and Other Dementias 05/2014; · 1.43 Impact Factor
Publique-Ho ˆpitauxdeParis(AP-HP),Pitie ´-Salpe ˆtrie `reHospitalGroup,InstituteforMemoryandAlzheimer’sDisease,F75013Paris,France,4InsermU975,
F75013Paris,France,and5AP-HP,Pitie ´-Salpe ´trie `reCharlefoixHospitalGroup,Serviced’ExplorationsFonctionnellesNeurologiquesetCardiovasculaires,
Episodic memory impairment is a hallmark for early diagnosis of Alzheimer’s disease. Most actual tests used to diagnose Alzheimer’s
have the highest predictive power for mild Alzheimer’s disease diagnosis versus frontotemporal lobar degeneration and normal aging.
Pathophysiology in Alzheimer’s disease (AD) is associated with
medial temporal lobe dysfunction (Seab et al., 1988; Jobst et al.,
1992; Scahill et al., 2002; Thompson et al., 2003). Already during
the initial stages of AD, tau pathology is found in the medial
temporal lobe (Braak and Braak, 1991; Van Hoesen et al., 1991).
Marked hippocampal atrophy with tau- and amyloid-related le-
sions are specific to AD. Indeed, hippocampal atrophy specifi-
cally predicts conversion to AD in mild cognitive impairment
function differentiates AD from normal aging and frontotempo-
ral lobe degeneration (FTLD)— the second most common de-
et al., 2008).
This hippocampal locus of early AD pathology is consistent
with spatiotemporal orientation impairments in everyday activ-
ities (Pai and Jacobs, 2004), such as difficulties in finding one’s
AD—the symptomatic predementia phase (deIpolyi et al., 2007;
respondingly, patients with mild AD are impaired for spatial
memory (Kessels et al., 2005; Hort et al., 2007; Cushman et al.,
Kalova ´ et al., 2005; deIpolyi et al., 2007).
hippocampal-dependent episodic memory impairment appears
ive criterion based on biomarkers or genetics, for early diagnosis
of AD. To take care of Alzheimer patients as early as possible, a
ease early on is of major importance.
However, defining a behavioral task that is sufficient to pro-
vide a satisfactory diagnosis is still a challenge. Limitations of the
memory tests used in clinic primarily concern their unsatisfac-
2000; Simons et al., 2002; Thompson et al., 2005; Tierney et al.,
2005). One possible reason for this is that memory tests used in
clinic do not model proper hippocampal function. Indeed, most
tests can be resolved without reference to a spatiotemporal con-
text, which precisely depends on hippocampal function (for re-
view, see Burgess et al., 2002).
Our aim was to develop a sensitive and specific behavioral
nonverbal marker of mild AD. We hypothesized that AD would
be best diagnosed by a test assessing spatiotemporal memories
acquired through active navigation, because this requires hip-
B.D., and L.R.-R. contributed unpublished reagents/analytic tools; V.B. and L.R.-R. analyzed data; V.B., B.D., and
This work was supported by Fondation Recherche Me ´dicale (programme Longe ´vite ´ Cognitive et
neurosensorielle-DLC20060206428) grants, Agence Nationale de la Recherche (ANR Young Researcher 07-JCJC-
JarlierforhishelponcomputerprogrammingandBe ´ne ´dicteBabayanforcarefulreadingofthemanuscript.Wealso
1942 • TheJournalofNeuroscience,February8,2012 • 32(6):1942–1952
pocampal function (Maguire et al., 1998; Burgess et al., 2002;
Iglo ´i et al., 2010).
Here we use a paradigm consisting in the creation of a non-
verbal spatiotemporal memory using the Starmaze navigation
task (Rondi-Reig et al., 2006; Iglo ´i et al., 2009, 2010), which acti-
vates the hippocampus in young healthy subjects (Iglo ´i et al.,
2010). We tested three age groups of healthy volunteers and
FTLD, amnestic MCI (aMCI), and AD patients to disentangle
age- and AD pathology-related impairments compared with a
battery of other standard neuropsychological tests.
Patients with AD (N ? 16, 8 males and 8 females), amnestic mild cogni-
tive impairment (aMCI, N ? 14, 10 males and 4 females) or FTLD (N ?
Salpe ˆtrie `reHospital.Sixty-threehealthycontrolsalsoparticipatedinthis
study. They were divided into three age groups (20–39, N ? 20, 9 males
N ? 24, 11 males and 13 females).
interview included an investigation of depression symptoms and, when
the neurologist judged necessary, the Montgomery Åsberg Depression
Rating Scale (Montgomery and Åsberg, 1979) was used to assess depres-
All subjects (patients and controls) underwent a neuropsychological ex-
amination that included the Mini Mental State Examination (MMSE)
(Grober and Buschke, 1987) for verbal episodic memory; the delayed
tal Assessment Battery (FAB) (Dubois et al., 2000) for executive func-
tions; the Corsi Block-Tapping Task (Corsi, 1972) with the forward
version (CBT-F, testing the exact recall of a spatial sequence) for visu-
ospatial span, and the backward version (CBT-B, testing the recall of a
spatial sequence backwards) for working memory (Kessels et al., 2008).
ity of the disease was assessed by the Clinical Dementia Rating (CDR)
Fluency test (letter S and category: fruit in 2 min) (Kremin et al., 1999).
an additional specific neuropsychological battery was administered to
increase the specificity of the clinical diagnosis using tests to assess or-
bitofrontal function for frontal variant of FTLD, semantic memory for
semantic dementia, and language for progressive non-fluent aphasia.
Subjects who presented any of the following were excluded: 1) sys-
temic illnesses that could interfere with cognitive functioning; 2) major
depression; 3) score on MMSE lower than 15; 4) history of stroke, 5)
clinical or neuroimaging evidence of focal lesions or presence of subcor-
tical vascular lesions on brain MRI; 6) visual deficit that could interfere
with the performance on the experimental task (all subjects should have
normal vision or corrected to normal vision).
Patients with AD (N ? 16) fulfilled the NINCDS-ADRDA (Alzhei-
mer’s Disease and Related Disorders Association) criteria (McKhann et
al., 1984) and the new research criteria for AD (Dubois et al., 2010). All
AD patients had progressive amnesia of the medial temporal type
(Dubois et al., 2007) characterized by a low free recall not normalized
with cueing (Dubois and Albert, 2004), and at least one positive in vivo
marker of AD pathology among the following: CSF amyloid ?; total tau
and phospho-tau. All AD patients had a CDR score ?0.5.
Patients with aMCI (N ? 14) had progressive amnesia of the medial
ment of normal daily life activities. Their CDR was of 0.5.
Patients with FTLD (N ? 11) were included according to consensual
criteria (Neary et al., 1998; McKhann et al., 2001). This group included
patients presenting the following clinical profiles: (1) frontal variant of
FTLD (N ? 5) characterized by decline in behavior and executive func-
tioning, (2) semantic dementia (N ? 3), associated with fluent progres-
speech and impaired grammatical comprehension.
Healthy adults were also included (N ? 63), among whom there were
24 healthy old adults (60–80 years old), age-matched to patients. The
young adults were recruited from university or public announcements.
Old adults were recruited from social clubs for retired people and none
had impaired activities of daily living. All healthy controls underwent a
short clinical interview to exclude medical disorders that could interfere
assessment as patients. Normal controls had no neurological complaints
nor symptoms of depression, had normal neuropsychological examina-
tions, and had preserved daily life functioning (CDR ? 0).
A score of 0 corresponded to no or sparse computer experience. If the
subject frequently used a computer, a score of 1 was given. Playing 2D
computer games corresponded to a score of 2, and playing games imple-
mented in virtual reality corresponded to a score of 3. Patients and age-
matched controls (60–80 group) were matched for computer ability
according to this scale.
We obtained written informed consent from all subjects according to
the Declaration of Helsinki (BMJ 1991; 302: 1194) and the study was
approved by the Pitie ´ Salpe ˆtriere Ethics Committee.
The virtual reality Starmaze, designed with 3D StudioMax (Autodesk For-
tune 1000) and made interactive with Virtools (v3.5) (Dassault Syste `mes),
comprised five central alleys forming a pentagon and five alleys radiating
to move their viewpoint forward or backward or to turn left or right; they
were placed between the ends of adjacent alleys and every cue was present
twice around the maze, so that solving the task required knowledge of the
cue. Participants were told to find a goal that would always be at the same
providing feedback. Participants knew that the environment would not
change during the experiment. Before testing started, subjects spent a few
aspects of the task. They were taught to observe the landscape by turning
without moving forward. As soon as subjects were comfortable with the
The experiment consisted of learning trials followed by the temporal
and spatial memory tests (see Fig. 1C for complete trial order). During
the learning phase, successful navigation could be supported by either
type of representation: sequential egocentric (sequence of body-turns),
allocentric (location relative to environmental cues) (see also Iglo ´i et al.,
learned both the sequential egocentric and the allocentric strategies in
parallel (Iglo ´i et al., 2009). Therefore, they learned a sequence of move-
ments leading to the goal, and also the configuration of external land-
marks surrounding the maze.
The learning phase consisted of 11 learning trials. A trial ended either
when a subject reached the goal location, or after the 90 s time-limit,
except if after the 90 s time-limit the subject had not traveled the mini-
mum distance in the maze (corresponding to four central and three
peripheral alleys); in which case the trial ended when this amount of
distance was traveled. One exception was the first three learning trials: if
subjects failed to reach the goal within these conditions on time and
by going straight forward.
Every 200 ms, the exact position of the subject was registered in a
Cartesian coordinate system. Learning performance was measured by
Bellassenetal.•DifferentialADDiagnosis J.Neurosci.,February8,2012 • 32(6):1942–1952 • 1943
two parameters: percentage of successful trials and percentage of direct
trials (Fig. 2). Successful trials corresponded to the trials where a subject
reached the goal within the time or distance limit. Direct trials corre-
sponded to the trials where a subject reached the goal without entering
any peripheral alley different from the arrival alley.
An exploration mark was defined as the number of entries in periph-
eral alleys (Fig. 1, alleys 1, 3, 5, 7, and 9) during the first trial of the
learning phase. This score was previously used by Moffat et al. (2001).
This measure was used to control that old and young subjects did not
were equally able to move and turn in the virtual environment.
Temporal memory tests. The temporal memory tests, called sequential navi-
as the one performed during the last trial of the learning phase (learn-
ing trial 11 or T11).
trial (T11). To test for the temporal aspect of sequential navigation, all
environmental cues were removed (Fig. 1A1). The trial ended when a
peripheral alley was fully visited.
Route tracing. In the route tracing test, subjects had to trace the route
Starmaze provided to the subject (Fig. 1A2). Correct answers were not
provided after these tests.
Both temporal tests are scored using the repeated path score. The
sequence performed on T11 is taken as reference. We compare the be-
havior of the subject at each choice point with the behavior at the same
choice point during the reference trial. At a given choice point, if the
subject reproduces the same path as during the reference trial, it is con-
sidered as a “correct turn” and we allocate a mark of 100. If the subject
moves away from the T11 pathway, a mark of 0 is allocated. The average
of the marks for all choice points yields the repeated path score. With
such scoring, a repeated path score of 100 means that the subject has
of directness of path) use allocentric or sequential egocentric navigation
strategies, the repeated path score reflects the use of the sequential ego-
centric strategy based on temporal order memory, be it optimal or not.
To minimize the impact on the repeated path score of random navi-
gation that characterizes lost subjects, the repeated path score was com-
puted on the portion of the performed path comprised between the
starting point and the first extremity of a peripheral alley visited.
To control for an accidental error in one of the temporal tests, we
considered the mean repeated path score obtained on both sequential
and route tracing tests as a better index to assess sequence memory def-
icit, than each of these scores taken separately.
in the environment and to specify their number (Fig. 1A3).
This test was evaluated by the percentage of correctly and freely re-
Each groove of trees, each individual village and each mountain range
were considered as a single object (Fig. 1B).
to the goal (Fig. 1A4). The goal, placed in regards to the departure point
that had been defined during the route tracing task, was shown to the
The “where” score was equal to the number of correctly placed cues,
averaged out by the total number of visual cues (8). It evaluated the
capacity to encode an allocentric map (Moffat and Resnick, 2002).
group of healthy adults (60–80). A p ? 0.05 level of significance was
chosen. ANOVA tests were conducted to compare performances among
1944 • J.Neurosci.,February8,2012 • 32(6):1942–1952 Bellassenetal.•DifferentialADDiagnosis
groups. After a significant main effect, Scheffe post hoc tests were per-
formed. To control for computer experience, an ANCOVA analysis was
Receiver operating characteristic
A Receiver operating characteristic (ROC) analysis was performed to
evaluate the discriminating power of each neuropsychological test taken
on the ROC curve that maximized both sensitivity and specificity.
To investigate whether the navigation task provided additional discrim-
inant information to standard neuropsychological tests, a discriminant
analysis was performed (Wilk’s method) on standard neuropsychologi-
for Windows 5.1, Statsoft, Inc) for the 3 groups: AD, 60–80, and FTLD.
We first entered all parameters in a preliminary discriminant analysis:
model 1 with neuropsychological tests only (12 parameters), and model
2 with neuropsychological tests and Starmaze parameters (18 parame-
ters) to determine the most discriminant parameters. Because the num-
ber of variables entered in a model impacts on its discriminating power,
we then ran a second definitive discriminant analysis including the 6
most discriminant parameters of the prelimi-
nary discriminant analysis to have the same
number of parameters in both models.
Wilk’s lambda index (where a partial Wilk’s
lambda score of 0 referred to perfect discrimi-
nation) and Youden index (Y ? Sensitivity ?
Specificity ? 1) were used to measure each
model’s discriminating power. To better un-
derstand which groups of subjects were best
discriminated by one variable, we performed a
than on all three patients groups.
imental tests were sensitive, a factor analysis
was performed on the 10 neuropsychological
tests and the 6 variables from the Starmaze
task. Because performances of temporal tests
had ceiling effects in young adults, only the
three groups 60–80, AD, and FTLD were con-
sidered. Factor analysis was based on principal
component analysis with varimax rotation.
termined the number of factors extracted.
Neuropsychological characteristics of the
groups are shown in Table 1.
Healthy adults were divided into three
age groups: 20–39, 40–59, and 60–80
years old. There were significant age ef-
fects for computer experience (F(2,60)?
19.9, p ? 10?3), with younger subjects
having more computer experience. Pa-
did not differ in terms of education level
(F(3.61)? 0.32, p ? 0.8), computer expe-
rience (F(3.61)? 1.30, p ? 0.27), or age
(F(3.61)? 0.31, p ? 0.81). MMSE was sig-
nificantly lower in AD and FTLD groups,
but not in the aMCI group, compared
with the 60–80 group (F(3,61)? 13.3, p ?
10?6) (Table 1).
Exploration activity did not differ among patient groups and the
60–80 control group (F(3,61)? 0.35, p ? 0.78, Fig. 2C).
ing effect, determined by a linear regression over the 3 blocks of
rameters: the percentage of successful trials (B coefficient ? 3,11,
Temporal memory tests
timal performance for the sequential navigation task (Fig. 3A,
Bellassenetal.•DifferentialADDiagnosis J.Neurosci.,February8,2012 • 32(6):1942–1952 • 1945
the 60–80 group did not fully succeed this trial.
For patients, there was a significant effect of diagnosis (F(3,61)?
13.3, p ? 10?4) where aMCI and AD patients were each signifi-
cantly impaired relative to controls (Scheffe’s test: p ? 0.02 for
all) and AD patients were impaired relative to FTLD group
(Scheffe’s test: p ? 0.005). These results remained significant
after controlling for computer experience (F(3,60)? 16.2, p ?
10?4), mean repeated path score during the learning phase
learning phase (F(3,60)? 21.5, p ? 10?7).
ing performance (p ? 0.2), as opposed to a significant patient
main effect revealed that AD patients were impaired relative to
the control and FTLD groups (Scheffe’s test: p ? 0.002 for all)
controls (p ? 2.10?4) and nonsignificantly to FTLD (Fig. 3A,
middle). The repeated path scores for the route tracing task and
sequential navigation task correlated significantly (r ? 0.61,
p?10?5). These results on patient groups remained significant
after controlling for computer experience (F(3,60)? 16.7, p ?
10?4), mean repeated path score during the learning phase
learning phase (F(3,60)? 27.1, p ? 10?7).
During normal aging, there was a clear trend for impairment
of temporal memory, evaluated overall by the mean value of
tests, without however reaching statistical significance (F(2,60)?
3.1, p ? 0.051). AD patients and, importantly, aMCI patients,
Diagnostic value of mean performances. The majority of aMCI
and AD patients performed unsuccessfully on both temporal
tests (50% and 75%, respectively). Conversely, neither healthy
a majority performed successfully on both tests (at least 64% of
double successes for each group) while a minority performed
group, 36% in the FTLD group).
For AD detection among FTLD and age-matched healthy
adults, a cutoff score of 66.5/100 for the temporal memory score
(i.e., mean of the two temporal memory tests’ performances)
yielded maximum sensitivity (87.5%) and specificity (91.4%)
of 60.5% yielded a maximum sensitivity of 61% and a specificity
of 100%. Seven aMCI patients (50% of the aMCI group) were
AD while the 2 others were cognitively stable. These 5 converters
all had scores below the cutoff of 60.5% (see color plots, Fig. 3A,
“What” memory test
There was a significant effect of age group for the free recall of
28.8(1.2) 27.9(1.4)28.3(1.2)25.9(3.4)22.8(3.5) 24.9(2.5)
35.3(1.0) 34.3(1.7)33.6(1.7)* 31.7(4.4)25.9(9.4)27.5(5.6)
1946 • J.Neurosci.,February8,2012 • 32(6):1942–1952Bellassenetal.•DifferentialADDiagnosis
age-matched control group for the free recall of objects, with a
mean number of freely recalled cues of 3.1 ? 0.41 of 8 cues
recalled (Fig. 3B).
Spatial memory test: “where”
There was no effect of age for the positioning of cues (“where”)
p ? 10?7). Scheffe post hoc tests of the main effect revealed that
AD patients were significantly impaired relative to controls and
FTLD patients (p ? 0.03 for both). AD patients placed correctly
11 ? 5% of the cues, compared with 32 ? 3% for controls, 26 ?
7% for aMCI patients, and 32 ? 6% for FTLD patients (Fig. 3C).
ing power of neuropsychological tests with that of Starmaze sub-
tests (Table 2). The highest Youden index (Y) of all the tests was
found for the temporal memory tests (Y ? 0.79) followed by the
more discriminating than each of the temporal tests, without
however reaching statistical significance. An explanation for this
poral test in the different groups. In the aMCI and AD groups,
failure on both temporal tests was more frequent than failure on
only one temporal test (aMCI patients: 50% vs 28.5%; AD pa-
Sequentialnavigation 0.89 0.05
50.1 91.4 0.41
81.0 42.9 0.24
93.8 57.1 0.51
97.5 48.6 0.46
81.3 60.1 0.41
93.8 62.9 0.57
81.3 68.6 0.49
93.8 57.1 0.51
81.3 91.2 0.72
87.5 82.9 0.70
81.3 88.6 0.70
93.8 74.3 0.68
87.5 85.7 0.73
87.5 91.4 0.79
Bellassenetal.•DifferentialADDiagnosisJ.Neurosci.,February8,2012 • 32(6):1942–1952 • 1947
tients: 75% vs 18.7%, respectively). This suggests that assessing
temporal memory twice is more discriminating than only once,
as it reduces the impact of single errors that may be accidental.
tion value for the differential diagnosis of early AD to that of
standard neuropsychological tests used in clinic, a discriminant
analysis (DA) was performed on AD, FTLD, and 60–80 groups.
Two models with the same number of variables were com-
pared: model 1 with neuropsychological tests and without
and with Starmaze parameters.
DA was performed on the three groups (AD, FTLD, 60–80) in-
cluding all variables. In model 1 of the preliminary DA, all neu-
ropsychological and demographic variables were included; in
model 2 of the preliminary DA, the latter variables supplied with
performance variables from the Starmaze task were: (1) percent-
score; (5) the spatial memory score, and (6) temporal memory
score. The rationale for including the performances on trial 11,
two different strategies performed at an equivalent time during
the experience; on the one hand an undetermined strategy (as
measured by trial 11), and on the other hand, a strategy based on
sequence or spatial memory.
the preliminary DA were entered into the definitive DA con-
ducted on the three groups (Fig. 4). In model 1, sensitivity and
specificity values reached 60% and 97%, respectively (Youden
percentage of direct paths on learning trial 11 as Starmaze per-
formance parameters, overall discrimination was higher than in
the DA of the temporal memory component with the percentage
of direct paths associated with other standard neuropsychologi-
cal tests allowed to fully discriminate 60–80, FTLD and AD
groups (see color plots in Fig. 4).
Finally, in a DA on model 2 conducted on pairs of groups,
temporal memory score was the most significant variable for AD
the percentage of direct paths (Fig. 4, bottom).
To infer the cognitive functions the experimental tests were sen-
sitive to, a factor analysis with all neuropsychological and exper-
imental tests was performed (Table 4). This identified 4 factors
with eigenvalues ?1, that explained 72% of total variance. The
first factor explained 47% of variance and included verbal mem-
ory (FCSRT) subtests (factor loading ? 0.84), the temporal
memory score (factor loading ? 0.73) and the spatial memory
test (factor loading ? 0.54). This factor essentially constitutes a
simple index of memory. The other factors explained ?10%
variance each, essentially corresponding to general cognitive/
visuoconstructive functions, encoding of the environment,
and executive function.
We hypothesized that testing spatiotemporal memory in a non-
verbal and active navigation task would be appropriate to assess
from FTLD and healthy aging. We used the Starmaze navigation
spatiotemporal memory, later tested for temporal (“when”) and
spatial (“where”) components.
1948 • J.Neurosci.,February8,2012 • 32(6):1942–1952 Bellassenetal.•DifferentialADDiagnosis
specific changes, independently of aging in a spatiotemporal
tial egocentric navigation strategies which both depend on the
hippocampus(Iglo ´ietal.,2010)andareacquiredinparallel(Iglo ´i
et al., 2009) in healthy young subjects.
to differentiate AD from aMCI, FTLD, and normal aging, and
that this temporal memory test, along with the percentage of
direct paths, increases the discriminating power of other neuro-
psychological tests to 100%.
There were no significant age- or patient-group differences
in the motor aspects of the task assessed by the analysis of their
specific impairments for temporal memory tests do not reflect a
difference in computer experience, since entering the latter as a
control variable in the analyses did not change any of the results.
Importantly, all groups of subjects showed a learning effect
during the navigation task (Fig. 2A,B). Nevertheless, perfor-
mance of the AD group was lower than the 60–80 and FTLD
groups as their percentage of direct paths to the goal was mark-
form of learning impairment presented here is consistent with
other studies’ results showing intact to-
pographical perception in AD (Bird et al.,
2010) and partially preserved route learn-
(Cushman et al., 2008).
Fig. 3C) in both aged (60–80) versus
younger (20–39) subjects, on the one
hand, and in AD patients compared with
FTLD patients and age-matched healthy
controls, on the other, are consistent with
previous findings of spatial processing
and Resnick, 2002; Driscoll and Suther-
land, 2005) and to AD pathology (Hort et
al., 2007; Bird and Burgess, 2008). Of
test cannot be explained by object mem-
not impaired for the “what” test (Fig.
3B). In agreement with the latter stud-
ies, the spatial memory score did not
have a sufficient predictive value to dis-
criminate AD from 60 to 80 and FTLD
groups (Fig. 3C; Table 2, ROC analysis:
sensitivity: 81.3%, specificity: 68.6%).
Studies assessing spatial memory in aging
and pathology have mostly focused on al-
locentric spatial processing (Moffat and
Resnick, 2002; Cushman et al., 2008; An-
tonova et al., 2009). Here, we additionally
focused on the temporal aspect of naviga-
tion (Eichenbaum, 2004; Fouquet et al.,
AD and even aMCI patients were im-
paired in both the sequential navigation
task and in the route tracing task. Assessing temporal memory
twice allowed differentiating accidental errors from memory er-
rors. These specific impairments of AD and aMCI groups on
temporal memory tests are consistent with their deficit for re-
et al., 2007) and in the sequential ordering of places in AD
(Kalova ´ etal.,2005).Theseobservationsmaybeexplainedbythe
fact that temporal sequence memory, which requires correct en-
coding where distinct time points are bound together to form a
temporal order memory (Fouquet et al., 2010), has been associ-
ated with hippocampal function in both rodents (DeCoteau and
Kesner, 2000) and humans (Kumaran and Maguire, 2006; Van
Opstal et al., 2008; Iglo ´i et al., 2010).
It is important to note that the temporal tests in the Starmaze
task is more than a simple temporal order test (e.g., assessing
order of words or scenes). The temporal order memory used
be defined as the capacity to distinguish between two spatial lo-
cations visited at different points in time. In this sense, it differs
from a simple test of temporal order by including two compo-
case does not refer to an allocentric representation of space but
for the number of variables. In both models, the 6 most discriminating variables from the preliminary discriminant analysis
groups. Graphs represent individual classifications along both factors extracted from the discriminant analysis. The more the
Bellassenetal.•DifferentialADDiagnosisJ.Neurosci.,February8,2012 • 32(6):1942–1952 • 1949
rather to the ability to maintain a representation of the order in
which location (i.e., intersection in our experiment) have been
experienced over time (Howland et al., 2008). This particular
both the hippocampus (Chiba et al., 1994; Gilbert et al., 2001;
Kesner et al., 2002) and the prefrontal cortex (Chiba et al., 1994;
Fuster, 2001; Hannesson et al., 2004) two regions particularly
sensitive to damage in AD patients. The temporal test in the
Starmaze task therefore requires recall of a spatiotemporal con-
text that involves the encoding of distances and directions along
the path. The complexity of this spatiotemporal memory tests
might be the key for better detection of Alzheimer’s disease than
simply temporal memory test.
is impaired only when important temporal monitoring is re-
quired (e.g., active search of items that have not been previously
visited) but not for the simple reproduction of sequences (Owen
et al., 1990). Results from this study are consistent with our re-
sults, since the temporal memory tests require few active moni-
toring and few executive function, the latter being impaired in
FTLD (Neary et al., 1998). Indeed, the temporal tests contain no
interfering cues (all alleys and intersections are identical) and no
choice of strategy.
As such, testing for temporal sequence memory in a naviga-
tion task appears to specifically target memory deficit in AD.
Also, the results of the factor analysis validated that the temporal
memory test, as well as the spatial memory test, essentially as-
sessed memory, as it is the case for the traditional test used to
assess episodic memory (FCSRT).
ory? All patients had performed the tested sequence at least 3
times before the last learning trial, so the temporal test does not
the classical definition of episodic memory as the ability to “re-
ral test assesses for the ‘what’,-‘where’-and-‘when’ components
of a personal experience. Also, it depends on hippocampal func-
tion as hippocampal activation during the recall of repeated
events and their context has been shown in the Starmaze task
(Iglo ´i et al., 2010). Overall, this suggests that the temporal test
shares crucial properties with episodic memory which could ex-
plain its sensitivity and specificity to AD diagnosis.
highly sensitive (87.5%) and specific (91.4%) to early AD when
compared with FTLD patients and healthy aged adults. Indeed,
the highest Youden index (Y) of all the tests was found for the
temporal memory score (Y ? 0.79), and the next most sensitive
and specific test was found for verbal recall (FCSRT-TR; Y ?
0.73) (Table 2). The temporal memory test added major contri-
bution to the discrimination of AD among healthy aged and
FTLD, as revealed by its low partial Wilk’s lambda value in the
discriminant analysis, Fig. 4). This indicates that the temporal
memory score was nonredundant with the other memory tests,
that is, it targeted components that were not captured in other
These additional components may arise from the fact that the
temporal tests model hippocampal function better than the lat-
ter. Indeed, to the contrary to the temporal tests, FCSRT and
delayed recall RCFT can be resolved without reference to a spa-
tiotemporal context, which precisely is hippocampus dependent
with the FCSRT task that consists in the recall of verbal lists
(Grober and Buschke, 1987) may be biased by the verbal aspects
of this task; differential familiarity with certain words as well as
both depend on extrahippocampal functions (Schweickert and
The temporal memory task also differentiated significantly
the aMCI group from the control group. Temporal sequence
memory impairments in MCI have been reported for sequential
orderingofplaces(Kalova ´ etal.,2005;Wenigeretal.,2011).Also,
we were able to follow 7 aMCI patients over 3 years. Five of them
converted later to AD, while 2 remained stable. The 5 converters
had temporal memory scores below the optimal cutoff for aMCI
detection among healthy aged adults (60.5%) (Fig. 3A, red
crosses). Overall, although the sample size was very small, these
results suggest that the temporal memory test might help to dif-
ferentiate future AD converters at the MCI stage from healthy
Finally, to evaluate the capacity of this test to depict very pro-
dromal AD, we also controlled for memory degradation in
healthy adults. Two adults from the 60–80 group showed iso-
lated and significant episodic memory impairments 18 months
later, without, however, reaching the criteria for aMCI. Both of
these potential converters had the lowest scores in their group
memory deficit might be tested as a preliminary detector of very
To conclude, the results show that a temporal memory test of
an experimentally controlled spatiotemporal memory discrimi-
nates AD and aMCI subjects from age-matched control subjects
and FTLD patients, with high sensitivity (87.5%) and specificity
(91.4%). Compared with the spatial memory test, the temporal
memory score is more specific to AD pathology and includes no
age-related deficit. Furthermore, this test had higher predictive
1950 • J.Neurosci.,February8,2012 • 32(6):1942–1952Bellassenetal.•DifferentialADDiagnosis
power than other standard neuropsychological memory tests,
and, associated with the latter, selectively raised the power of a
discriminant analysis to 100% showing that it added nonredun-
dant discriminant information to standard neuropsychological
Antonova E, Parslow D, Brammer M, Dawson GR, Jackson SH, Morris RG
(2009) Age-related neural activity during allocentric spatial memory.
Berg L (1988) Clinical Dementia Rating (CDR). Psychopharmacol Bull
Bird CM, Burgess N (2008) The hippocampus and memory: insights from
spatial processing. Nat Rev Neurosci 9:182–194.
Bird CM, Chan D, Hartley T, Pijnenburg YA, Rossor MN, Burgess N (2010)
Topographical short-term memory differentiates Alzheimer’s disease
from frontotemporal lobar degeneration. Hippocampus 20:1154–1169.
Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related
changes. Acta Neuropathol 82:239–259.
Burgess N, Maguire EA, O’Keefe J (2002) The human hippocampus and
spatial and episodic memory. Neuron 35:625–641.
Reig L (2005) Spatial navigation impairment in mice lacking cerebellar
LTD: a motor adaptation deficit? Nat Neurosci 8:1292–1294.
Chen P, Ratcliff G, Belle SH, Cauley JA, DeKosky ST, Ganguli M (2000)
Cognitive tests that best discriminate between presymptomatic AD and
those who remain nondemented. Neurology 55:1847–1853.
Cherrier MM, Mendez M, Perryman K (2001) Route learning performance
in Alzheimer disease patients. Neuropsychiatry Neuropsychol Behav
ChibaAA,KesnerRP,ReynoldsAM (1994) Memoryforspatiallocationasa
tal cortex. Behav Neural Biol 61:123–131.
Chupin M, Ge ´rardin E, Cuingnet R, Boutet C, Lemieux L, Lehe ´ricy S, Benali
H, Garnero L, Colliot O (2009) Fully automatic hippocampus segmen-
ment applied on data from ADNI. Hippocampus 19:579–587.
Corsi P (1972) Human memory and the medial temporal region of the
brain. Abstracts Int 34:891B.
Cushman LA, Stein K, Duffy CJ (2008) Detecting navigational deficits in
cognitive aging and Alzheimer disease using virtual reality. Neurology
DeCoteau WE, Kesner RP (2000) A double dissociation between the rat
hippocampus and medial caudoputamen in processing two forms of
knowledge. Behav Neurosci 114:1096–1108.
deIpolyi AR, Rankin KP, Mucke L, Miller BL, Gorno-Tempini ML (2007)
Spatial cognition and the human navigation network in AD and MCI.
Dere E, Huston JP, De Souza Silva MA (2005) Episodic-like memory in
ory. Brain Res Brain Res Protoc 16:10–19.
Driscoll I, Sutherland RJ (2005) The aging hippocampus: navigating be-
tween rat and human experiments. Rev Neurosci 16:87–121.
Drzezga A, Grimmer T, Henriksen G, Stangier I, Perneczky R, Diehl-Schmid
J, Mathis CA, Klunk WE, Price J, DeKosky S, Wester HJ, Schwaiger M,
Kurz A (2008) Imaging of amyloid plaques and cerebral glucose metab-
olism in semantic dementia and Alzheimer’s disease. Neuroimage
Dubois B, Albert ML (2004) Amnestic MCI or prodromal Alzheimer’s dis-
ease? Lancet Neurol 3:246–248.
DuboisB,SlachevskyA,LitvanI,PillonB (2000) TheFAB:aFrontalAssess-
ment Battery at bedside. Neurology 55:1621–1626.
Dubois B, Feldman HH, Jacova C, Dekosky ST, Barberger-Gateau P, Cum-
P (2007) Research criteria for the diagnosis of Alzheimer’s disease: re-
vising the NINCDS-ADRDA criteria. Lancet Neurol 6:734–746.
Dubois B, Feldman HH, Jacova C, Cummings JL, Dekosky ST, Barberger-
pel H, Jicha GA, Meguro K, O’Brien J, Pasquier F, Robert P, Rossor M,
Salloway S, Sarazin M, et al. (2010) Revising the definition of Alzhei-
mer’s disease: a new lexicon. Lancet Neurol 9:1118–1127.
EichenbaumH (2004) Hippocampus:cognitiveprocessesandneuralrepre-
sentations that underlie declarative memory. Neuron 44:109–120.
Elfgren C, Brun A, Gustason L, Johanson A, Minthon L, Passnt U, Risberg J
(1994) Neuropsychological tests as discriminators between dementia of
Alzheimer type and frontotemporal dementia. Int J Geriatric Psychiatry
Folstein MF, Folstein SE, McHugh PR (1975) “Mini-mental state”. A prac-
tical method for grading the cognitive state of patients for the clinician.
J Psychiatr Res 12:189–198.
Fouquet C, Tobin C, Rondi-Reig L (2010) A new approach for modeling
episodic memory from rodents to humans: the temporal order memory.
Behav Brain Res 215:172–179.
Fuster JM (2001) The prefrontal cortex—an update: time is of the essence.
Gilbert PE, Kesner RP, Lee I (2001) Dissociating hippocampal subregions:
double dissociation between dentate gyrus and CA1. Hippocampus
Grober E, Buschke H (1987) Genuine memory deficits in dementia. Dev
Hannesson DK, Vacca G, Howland JG, Phillips AG (2004) Medial prefron-
tal cortex is involved in spatial temporal order memory but not spatial
recognition memory in tests relying on spontaneous exploration in rats.
Behav Brain Res 153:273–285.
Hort J, Laczo ´ J, Vyhna ´lek M, Bojar M, Bures J, Vlcek K (2007) Spatial nav-
U S A 104:4042–4047.
HowlandJG,HarrisonRA,HannessonDK,PhillipsAG (2008) Ventralhip-
pocampal involvement in temporal order, but not recognition, memory
for spatial information. Hippocampus 18:251–257.
Iglo ´i K, Zaoui M, Berthoz A, Rondi-Reig L (2009) Sequential egocentric
strategy is acquired as early as allocentric strategy: Parallel acquisition of
these two navigation strategies. Hippocampus 19:1199–1211.
Iglo ´i K, Doeller CF, Berthoz A, Rondi-Reig L, Burgess N (2010) Lateralized
human hippocampal activity predicts navigation based on sequence or
place memory. Proc Natl Acad Sci U S A 107:14466–14471.
Jobst KA, Smith AD, Szatmari M, Molyneux A, Esiri ME, King E, Smith A,
JaskowskiA,McDonaldB,WaldN (1992) Detectioninlifeofconfirmed
atrophy by computed tomography. Lancet 340:1179–1183.
Kalova ´ E, Vlcek K, Jarolímova ´ E, Bures J (2005) Allothetic orientation and
sequential ordering of places is impaired in early stages of Alzheimer’s
disease: corresponding results in real space tests and computer tests. Be-
hav Brain Res 159:175–186.
Kesner RP, Gilbert PE, Barua LA (2002) The role of the hippocampus in
memory for the temporal order of a sequence of odors. Behav Neurosci
KesselsRP,FeijenJ,PostmaA (2005) Implicitandexplicitmemoryforspa-
tial information in Alzheimer’s disease. Dement Geriatr Cogn Disord
Kessels RP, van den Berg E, Ruis C, Brands AM (2008) The backward span
of the Corsi Block-Tapping Task and its association with the WAIS-III
Digit Span. Assessment 15:426–434.
Kremin H, Perrier D, De Wilde M (1999) DENO-100—Paradigme expe ´ri-
mental et test clinique de de ´nomination contro ˆle ´e: effet relatif de 7 vari-
de ´ge ´ne ´ratives. Rev Neuropsychol 439–440.
Kumaran D, Maguire EA (2006) The dynamics of hippocampal activation
during encoding of overlapping sequences. Neuron 49:617–629.
Lezak MD (1983) Neuropsychological assessment, Ed 2. New York: Oxford
Longoni AM, Richardson JT, Aiello A (1993) Articulatory rehearsal and
phonological storage in working memory. Mem Cognit 21:11–22.
Maguire EA, Burgess N, Donnett JG, Frackowiak RS, Frith CD, O’Keefe J
(1998) Knowing where and getting there: a human navigation network.
McKhann GM, Albert MS, Grossman M, Miller B, Dickson D, Trojanowski
JQ (2001) Clinical and pathological diagnosis of frontotemporal de-
mentia: report of the Work Group on Frontotemporal Dementia and
Pick’s Disease. Arch Neurol 58:1803–1809.
McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM
(1984) Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-
ADRDA Work Group under the auspices of Department of Health and
Bellassenetal.•DifferentialADDiagnosis J.Neurosci.,February8,2012 • 32(6):1942–1952 • 1951
Human Services Task Force on Alzheimer’s Disease. Neurology
Moffat SD, Resnick SM (2002) Effects of age on virtual environment
place navigation and allocentric cognitive mapping. Behav Neurosci
Moffat SD, Zonderman AB, Resnick SM (2001) Age differences in spatial
memory in a virtual environment navigation task. Neurobiol Aging
MorrisJC (1993) TheClinicalDementiaRating(CDR):currentversionand
scoring rules. Neurology 43:2412–2414.
Kertesz A, Robert PH, Albert M, Boone K, Miller BL, Cummings J, Ben-
sonDF (1998) Frontotemporallobardegeneration:aconsensusonclin-
ical diagnostic criteria. Neurology 51:1546–1554.
Ohno M, Chang L, Tseng W, Oakley H, Citron M, Klein WL, Vassar R,
Disterhoft JF (2006) Temporal memory deficits in Alzheimer’s mouse
Owen AM, Downes JJ, Sahakian BJ, Polkey CE, Robbins TW (1990) Plan-
ning and spatial working memory following frontal lobe lesions in man.
Pai MC, Jacobs WJ (2004) Topographical disorientation in community-
residing patients with Alzheimer’s disease. Int J Geriatr Psychiatry
Rabinovici GD, Furst AJ, O’Neil JP, Racine CA, Mormino EC, Baker SL,
Chetty S, Patel P, Pagliaro TA, Klunk WE, Mathis CA, Rosen HJ, Miller
BL, Jagust WJ (2007) 11C-PIB PET imaging in Alzheimer disease and
frontotemporal lobar degeneration. Neurology 68:1205–1212.
ReyA (1993) Psychologicalexaminationoftraumaticencephalopathy.Clin
Rondi-Reig L, Petit GH, Tobin C, Tonegawa S, Mariani J, Berthoz A (2006)
Impaired sequential egocentric and allocentric memories in forebrain-
specific-NMDA receptor knock-out mice during a new task dissociating
strategies of navigation. J Neurosci 26:4071–4081.
Puel M, Volteau M, Touchon J, Verny M, Dubois B (2007) Amnestic
syndrome of the medial temporal type identifies prodromal AD: a longi-
tudinal study. Neurology 69:1859–1867.
ScahillRI,SchottJM,StevensJM,RossorMN,FoxNC (2002) Mappingthe
fluid-registered serial MRI. Proc Natl Acad Sci U S A 99:4703–4707.
Schweickert R, Boruff B (1986) Short-term memory capacity: magic num-
ber or magic spell? J Exp Psychol Learn Mem Cogn 12:419–425.
Seab JP, Jagust WJ, Wong ST, Roos MS, Reed BR, Budinger TF (1988)
Quantitative NMR measurements of hippocampal atrophy in Alzhei-
mer’s disease. Magn Reson Med 8:200–208.
Recollection-based memory in frontotemporal dementia: implications
for theories of long-term memory. Brain 125:2523–2536.
(2004) Frontal assessment battery and differential diagnosis of fronto-
temporal dementia and Alzheimer disease. Arch Neurol 61:1104–1107.
Thompson JC, Stopford CL, Snowden JS, Neary D (2005) Qualitative neu-
ropsychological performance characteristics in frontotemporal dementia
and Alzheimer’s disease. J Neurol Neurosurg Psychiatry 76:920–927.
Thompson PM, Hayashi KM, de Zubicaray G, Janke AL, Rose SE, Semple
J, Herman D, Hong MS, Dittmer SS, Doddrell DM, Toga AW (2003)
Dynamics of gray matter loss in Alzheimer’s disease. J Neurosci
Tierney MC, Yao C, Kiss A, McDowell I (2005) Neuropsychological tests
accurately predict incident Alzheimer disease after 5 and 10 years. Neu-
Trivedi MA, Wichmann AK, Torgerson BM, Ward MA, Schmitz TW, Ries
ML, Koscik RL, Asthana S, Johnson SC (2006) Structural MRI discrim-
inates individuals with Mild Cognitive Impairment from age-matched
controls: a combined neuropsychological and voxel based morphometry
study. Alzheimers Dement 2:296–302.
TulvingE (2002) Episodicmemory:frommindtobrain.AnnuRevPsychol
Van Hoesen GW, Hyman BT, Damasio AR (1991) Entorhinal cortex pa-
thology in Alzheimer’s disease. Hippocampus 1:1–8.
VanOpstalF,VergutsT,OrbanGA,FiasW (2008) Ahippocampal-parietal
network for learning an ordered sequence. Neuroimage 40:333–341.
Weniger G, Ruhleder M, Lange C, Wolf S, Irle E (2011) Egocentric and
allocentric memory as assessed by virtual reality in individuals with am-
nestic mild cognitive impairment. Neuropsychologia 49:518–527.
1952 • J.Neurosci.,February8,2012 • 32(6):1942–1952Bellassenetal.•DifferentialADDiagnosis