doi:10.1111/psyg.
12301
ORIGINAL ARTICLE
Using virtual reality to distinguish subjects with multiple- but
not single-domain amnestic mild cognitive impairment from
normal elderly subjects
Alireza MOHAMMADI ,1 Mahmoud KARGAR2 and Ehsan HESAMI3
1
Neuroscience Research Center, Baqiyatallah Uni-
versity of Medical Sciences, 2Department of Speech
Therapy, School of Rehabilitation, Tehran Univer-
sity of Medical Sciences and 3Department of Speech
Therapy, University of Social Welfare and Rehabili-
tation Science, Tehran, Iran
Correspondence: Dr Alireza Mohammadi PhD,
Neuroscience Research Center, Baqiyatallah
University of Medical Sciences, Tehran, Iran. P.O. Box
19395-6558, Tehran 1413643561, Email: ar.
mohammadi@bmsu.ac.ir
Disclosure: The authors have no potential conflicts
of interest to declare regarding this article.
Received 12 May 2017; revision received 19 July 2017;
accepted 26 July 2017.
Key words: allocentric memory, egocentric memory,
mild cognitive impairment, spatial disorientation,
virtual maze, virtual neighbourhood.
INTRODUCTION
Mild cognitive impairment (MCI) is the limited deterio-
ration of cognitive abilities that is considered as a
transitional phase for the onset of Alzheimer’s dis-
ease (AD); it has a prevalence of 5.8–18.5% among
the elderly population (50–95 years).1–3 Given the
growing number of people with AD and the related
© 2018 Japanese Psychogeriatric Society
PSYCHOGERIATRICS 2018
Abstract
Aim: Spatial disorientation is a hallmark of amnestic mild cognitive impair-
ment (aMCI) and Alzheimer’s disease. Our aim was to use virtual reality to
determine the allocentric and egocentric memory deficits of subjects with
single-domain aMCI (aMCIsd) and multiple-domain aMCI (aMCImd). For this
purpose, we introduced an advanced virtual reality navigation task (VRNT)
to distinguish these deficits in mild Alzheimer’s disease (miAD), aMCIsd,
and aMCImd.
Methods: The VRNT performance of 110 subjects, including 20 with miAD,
30 with pure aMCIsd, 30 with pure aMCImd, and 30 cognitively normal con-
trols was compared. Our newly developed VRNT consists of a virtual neigh-
bourhood (allocentric memory) and virtual maze (egocentric memory).
Verbal and visuospatial memory impairments were also examined with Rey
Auditory-Verbal Learning Test and Rey-Osterrieth Complex Figure Test,
respectively.
Results: We found that miAD and aMCImd subjects were impaired in both
allocentric and egocentric memory, but aMCIsd subjects performed simi-
larly to the normal controls on both tasks. The miAD, aMCImd, and aMCIsd
subjects performed worse on finding the target or required more time in the
virtual environment than the aMCImd, aMCIsd, and normal controls, respec-
tively. Our findings indicated the aMCImd and miAD subjects, as well as the
aMCIsd subjects, were more impaired in egocentric orientation than allo-
centric orientation.
Conclusion: We concluded that VRNT can distinguish aMCImd subjects,
but not aMCIsd subjects, from normal elderly subjects. The VRNT, along
with the Rey Auditory-Verbal Learning Test and Rey-Osterrieth Complex
Figure Test, can be used as a valid diagnostic tool for properly distinguish-
ing different forms of aMCI.
challenges, it is necessary to identify these AD
patients as early as possible. As such, the diagnosis
of this transitional phase as a clinical state between
normal cognitive ageing and dementia can be impor-
tant to preventing recurrence and progression to
AD.4 MCI is categorized as amnestic (aMCI) or non-
amnestic (naMCI) and, based on the affected areas,
1
A. Mohammadi et al.
as occurring in a single domain or multiple domains.
Memory impairment alone is defined as single-
domain aMCI (aMCIsd), and memory loss plus other
cognitive impairments is defined as multiple-domain
aMCI (aMCImd). Similarly, naMCI is categorized as
single domain or multiple domain.5–7
Although aMCI patients may have normal general
cognitive functions and participate in activities of daily
living, they are usually diagnosed based on objective
memory complaints and subjective memory decline.3,8
Initial aMCI symptoms are often impaired memory
encoding and retrieval of contextual memory. In par-
ticular, persons with aMCI have problems remember-
ing the relationship between objects or between an
object and its context (associative memory).9 The cog-
nitive state of some of these patients appears to
remain constant or even return to normal, but more
than half progress to AD within 3–6 years.10–12
Working memory (WM), a central executive func-
tion, is a type of short-term memory with a limited
capacity; it is responsible for processing and manipu-
lating information.13,14 Although WM impairments are
well known in AD,15–18 few studies have evaluated
WM deficits in detail in individuals with aMCIsd and
aMCImd. Patalong-Ogiewa et al. found that patients
with MCI are impaired not only in WM but also in epi-
sodic memory, suggesting that the defect is not lim-
ited to the hippocampus.13 Additionally, magnetic
resonance imaging (MRI)-based brain volumetric
studies confirmed grey matter loss in the medial tem-
poral, parietal, and frontal areas of patients with
aMCI.19,20 Furthermore, individual performance dur-
ing a navigation task was confidently associated with
the grey matter volume of the dorsolateral prefrontal
cortex and hippocampus.21–23 Extensive neuroimag-
ing studies in adults showed that the dorsolateral
prefrontal cortex, ventrolateral prefrontal cortex, pre-
motor cortex, and posterior parietal cortex have criti-
cal roles in visuospatial working memory.24–27
Therefore, investigating spatial memory deficits in AD
and MCI is important for understanding the patho-
physiology of MCI and predicting dementia.1,28
Spatial disorientation is one of the early manifesta-
tions of AD and MCI, and it may become a diagnostic
marker for these diseases in the near future. This
problem occurs when patients are in an unfamiliar
place in the early stages of the disease, but it hap-
pens even in a familiar environment in advanced
stages.29,30 Allocentric and egocentric references are
2 © 2018 Japanese Psychogeriatric Society
two main types of spatial navigation. Allocentrism
(object- or environment-centred) refers to the ability
to experience the world from a more impersonal view
and more familiar environment; egocentrism (ego- or
body-centred) refers to the ability to see the world
from a personal view, which has a vital role in preser-
ving a stable moment-to-moment perception.31,32
Studies on the neural basis of spatial navigation have
indicated that the hippocampus and medial regions
of the temporal lobe are involved in allocentric repre-
sentations, whereas the parietal and striatal regions
are important in egocentric processing.33,34
Some studies previously reported the spatial navi-
gation deficits of MCI and AD patients 21,35–37; these
deficits are proportional to the right/left hippocampal
volume.23,35 Another report stressed the various diffi-
culties in topographic memory38; it recalled the for-
merly learned routes, landmarks, positions on the
map, and visuospatial attention.29,39–41 Weniger et al.
designed a virtual reality task to identify egocentric
and allocentric memory differences in aMCI and con-
trol subjects. The task was superior to earlier tasks,
but it did not assess the domains of the aMCI dis-
ease (i.e. aMCIsd vs aMCImd) or distinguish them
from AD.35,42 Similarly, reports from Kalová et al.,43
deIpolyi et al.,21 Cushman et al.,41 Nedelska et al.,23
Marková et al.,37 and Laczó et al. did not classify the
domains of the disease,44 but they did compare the
performance of patients with MCI or aMCI with that
of AD patients. In contrast, Hort et al. demonstrated
the spatial navigation differences between AD,
naMCI, aMCIsd, and aMCImd patients using the Hid-
den Goal Task (HGT), which had been previously
described by Stepankova.36,45
In this study, we aimed to compare the allocentric
and egocentric spatial navigation abilities of miAD,
aMCIsd, and aMCImd patients by investigating their
impairments. Because conversion to AD is more
common among aMCI patients (naMCI patients may
develop into non-AD dementias)46 and the similarity
in the performance between naMCI patients and
healthy controls,36,44 we did not investigate naMCI.
Also, based on previous studies that had similar
results from real and virtual spatial navigations,36,43,44
we did not assess navigation in the real environment.
Although HGT is a good task for evaluating allo-
centric and egocentric memory deficits, our
advanced virtual reality navigation task (VRNT) offers
several advantages, including a three-dimensional
 Multiple- but not single-domain aMCI

(3-D) and fully coloured environment and landmarks
that are more realistic looking than those of the com-
puter version of HGT. Moreover, HGT may be con-
siderably simpler than our VRNT. As such, it seems
that our VRNT is much more accurate than HGT in
distinguishing the subtypes of MCI. In this regard,
new virtual reality tools may be very useful in identify-
ing spatial navigation and memory deficits.
Given that aMCIsd is an earlier stage of AD than
aMCImd, we aimed to use virtual reality to detect
aMCIsd as a pre-aMCImd phase from cognitively nor-
mal controls (NC) and to prevent recurrence of the
disease and development of miAD. For this purpose,
we designed the VRNT with two virtual environments
(virtual neighbourhood and virtual maze) to separate
allocentric (virtual neighbourhood) and egocentric (vir-
tual maze) spatial navigation. The virtual neighbour-
hood was designed similarly to a real neighbourhood
and included appropriate navigational landmarks to
help subjects find their way. In contrast, there were
no landmarks in the virtual maze, and subjects had to
find the goal by recalling their route from memory. We
also investigated whether there was a specific com-
parative pattern of spatial navigation deficits among
aMCIsd, aMCImd, and miAD patients.
30 cognitively normal controls (NC) with no evidence
of cognitive impairment, were recruited from outpa-
tient services at the Baqiyatallah Hospital (Tehran,
Iran). Participants signed a standard informed con-
sent approved by the local ethics committee. Sub-
jects’ data are presented in Table 1.
Patients with miAD were diagnosed based on the
criteria of the Diagnostic and Statistical Manual of
Mental Disorders, 4th edition. The diagnosis of
aMCIsd and aMCImd were performed by an experi-
enced neurologist according to Petersen and Negash
and using the following criteria47: (i) the existence of
any subjective memory complaint; (ii) normal orienta-
tion and general cognitive performance according to
Mini-Mental State Examination (MMSE) score
(Persian version)48; (iii) normal score on language
ability using Boston Naming Test; and (iv) no known
causes of memory deficit (e.g. use of a medication
known to affect memory performance, major medical
or neurological illness).47 Inclusion criteria for NC
were as follows: (i) no established subjective memory
complaint; (ii) no approved recognizable cognitive
and memory impairment; (iii) MMSE score ≥27;
(iv) normal social functioning in the community; and
(v) no active neurologic or psychiatric disease.49

Procedure
METHODS All subjects underwent neuropsychological assess-
Participants ment and completed a visuospatial navigation task
A total of 110 subjects, including 20 with miAD, using our recently developed VRNT. It took 12 months
30 with pure aMCIsd, 30 with pure aMCImd, and to administer the tests and evaluate all subjects.

Table 1 Demographic and neuropsychological characteristics of the groups

Characteristics NC (n = 30) miAD (n = 20) aMCImd (n = 30) aMCIsd (n = 30)
Age (years) 69.867  1.432 73.65  2.476* 70.067  1.638*** 70.000  1.681***
MMSE 28.067  1.014 19.3  1.031* 26.167  0.912*,*** 27.033  0.808*,***,*****
Education (years) 13.133  2.725 11.25  2.51** 12.033  2.326 12.967  2.341
Right/left handedness (n) 30/0 20/0 30/0 30/0
Women/men (n) 15/15 13/7 19/11 18/12
Duration of disorder (years) — 4.05  0.825 1.7  0.651*** 2.1  0.712***
RAVLT
Total score 47.133  1.074 18.15  1.814* 25.733  1.436*,*** 32.4  1.773*,***,****
Immediate recall scores 10.167  1.019 1.1  0.911* 2.7  0.749*,*** 4.833  0.874*,***,****
Delayed recall scores 9.667  0.994 0.55  0.759* 2.167  0.746*,*** 4.033  0.889*,***,****
R-OCFT
Immediate recall scores 10.033  0.927 2.55  0.759* 4.467  1.074*,*** 7.033  0.808*,***,****
Delayed recall scores 9.533  0.937 1.2  0.767* 3.333  0.758*,*** 6.233  0.773*,***,****

* P < 0.001 compared to the NC group. ** P < 0.05 compared to the NC group. *** P < 0.001 compared to the miAD group. **** P < 0.001 compared to the
aMCImd group. ***** P < 0.003 compared to the aMCImd group. All comparisons made based on ANOVA with Tukey’s post-hoc test. Handedness is based on
the Edinburgh Handedness Inventory. aMCImd, multiple-domain amnestic mild cognitive impairment; aMCIsd, single-domain amnestic mild cognitive impair-
ment; miAD, mild Alzheimer’s disease; MMSE, Mini-Mental State Examination; NC, cognitively normal controls; R-OCFT, Rey-Osterrieth Complex Figure Test;
RAVLT, Rey Auditory-Verbal Learning Test. Values are mean  SD.

© 2018 Japanese Psychogeriatric Society 3

A. Mohammadi et al.

Figure 1 The virtual neighbourhood. (a) First-person view. (b) Overhead view.

Neuropsychological assessment
The neuropsychological assessment covered the fol-
lowing cognitive domains: (i) verbal memory, as
determined by the Rey Auditory-Verbal Learning Test
(RAVLT) (i.e. the sum of five trials, recall after inter-
vention, delayed recall after 30 min, and memory rec-
ognition)50; (ii) non-verbal memory, as assessed by
the Rey-Osterrieth Complex Figure Test (R-OCFT)
immediate recall; (iii) visuospatial memory, as evalu-
ated by R-OCFT 30-min delayed recall51; and
(iv) overall cognitive function, as measured by the
MMSE.48
Virtual reality environment task
Test design
Computer-based virtual reality environments have
already been described and used as tools for visuo-
spatial memory assessment in previous studies.42,52
These virtual reality environments are colourful, tex-
tured, and 3-D, and they also offer a first-person
view. Actions in the environment can be controlled
by individuals using a joystick.
Our advanced VRNT was designed with two virtual
environments (virtual neighbourhood and virtual
maze) to assess allocentric (virtual neighbourhood)
and egocentric (virtual maze) spatial navigation. The
virtual neighbourhood was modelled on the natural
environment (i.e. a real neighbourhood) and included
pertinent navigational landmarks to help subjects find
their routes (Fig. 1). In contrast, the virtual maze did
not contain any navigational landmarks so individuals
had to find the goal by recalling their route from the
memory (Fig. 2). Each of the virtual reality environ-
ments (virtual neighbourhood and virtual maze) com-
prised a 3-D first-person view and a two-dimensional
overhead view of the environment. First, the two-
dimensional overhead view was shown to the sub-
jects for 60 s, and then the 3-D first-person view was
presented. Subjects were then instructed to find the
specified goal (i.e. parking in the virtual neighbour-
hood; the ball in the virtual maze), which had been
marked on the 2-D overhead view. All subjects had
three trials to familiarize themselves with the task and
five trials for their assessment. Reactions and
response times were recorded.

Figure 2 The virtual maze. (a) First-person view. (b) Overhead view.

4 © 2018 Japanese Psychogeriatric Society


The 3-D first-person view of the virtual environment
were produced using Photoshop CS6 (Adobe, Tehran,
Tehran, Iran), AutoCAD (Autodesk, Tehran, Tehran,
Iran), and 3ds Max (Autodesk) software and run in the
Lumion 5.0 Pro editor (Tehran, Tehran, Iran). The size
of overhead view and first-person view images were
1280 × 720 pixels and 1920 × 1080 pixels, respec-
tively. Both the virtual neighbourhood and virtual maze
were presented, and the number of correct and incor-
rect responses and the completion time of each trial
were recorded. The results were processed to pro-
duce primary data tables for further statistical analysis.
Scoring
The number of correct responses and response time for
each subject were calculated for all trials of the virtual
neighbourhood and virtual maze. These were consid-
ered the dependent variables in the statistical analysis.
Analysis
One-way ANOVA was used to evaluate the group differ-
ences between normally distributed demographic and
neuropsychological variables and the performance of
miAD, aMCIsd, aMCImd, and NC on the VRNT (correct
responses and response time). Tukey’s post-hoc
method was applied for multiple comparisons of signif-
icant effects between groups. Pearson’s correlation
coefficient was used to determine the relationship
between neuropsychological parameters and the vir-
tual neighbourhood scores. All analyses were two-
tailed, and the significance level was defined as
P < 0.05. Statistical computations were carried out by
the SPSS version 22 (IBM (International Business
Machines Corporation), Tehran, Tehran, Iran.).
RESULTS
Descriptive statistics and neuropsychological
scores
Demographic analysis showed significant differences
between groups for age, MMSE score, duration of
the disorder (P < 0.001), and years of education
(P < 0.05). The subjects in the miAD, aMCIsd, and
aMCImd groups were predominantly women (65%,
63%, and 60%, respectively), whereas the NC group
had an equal number of men and women. More
detailed demographic characteristics of the subjects
are presented in Table 1.
© 2018 Japanese Psychogeriatric Society
Multiple- but not single-domain aMCI
Neuropsychological assessments indicated large
between-group effects. On all tests, the miAD group
had lower scores than the aMCIsd, aMCImd, and NC
subjects (P < 0.001). Similarly, both MCI subtypes
had lower scores than the NC group on all tests
(P < 0.001), but aMCIsd subjects performed signifi-
cantly better than the aMCImd subjects (P < 0.001).
Patients with miAD and aMCImd performed signifi-
cantly worse on the RAVLT (total scores, immediate
recall, and delayed recall) than the aMCIsd and NC
subjects (P < 0.001). Compared with the NC sub-
jects, the miAD, aMCIsd, and aMCImd subjects were
more impaired according to all of the R-OCFT subt-
ests (P < 0.001). Additionally, aMCImd subjects
scored significantly lower on all subtests of R-OCFT
than the aMCIsd subjects. These findings indicate
that the classification of the groups was reflected in
the results of neuropsychological tests. See Table 1
for more details about the neuropsychological fea-
tures of the groups.
Virtual reality tasks: virtual neighbourhood and
virtual maze
All subjects’ VRNT scores and response times for
the five trials were analyzed using one-way ANOVA
test followed by Tukey’s post-hoc test. The results
showed significant differences between groups in
the virtual neighbourhood and virtual maze tasks
(P < 0.001).
Virtual neighbourhood task
Comparisons of the scores among the miAD,
aMCIsd, aMCImd, and NC subjects across the five
trials showed significant differences on the virtual
neighbourhood task (P < 0.001). Further analysis
showed that miAD patients performed significantly
worse than the NC and aMCI subjects on the virtual
neighbourhood task (P < 0.001). Similarly, the
results indicated that the aMCImd subjects were
significantly more impaired than aMCIsd and NC
subjects (P < 0.001), but they were less impaired
than the miAD subjects (P < 0.001). Data indicated
that the miAD subjects completed their trials in a
longer time than the aMCI and NC subjects
(P < 0.001), and the aMCImd subjects had a slower
performance than the aMCIsd and NC subjects
(P < 0.001) (Table 2).
5
A. Mohammadi et al.

Table 2 Performance of groups on the VRNT (virtual neighbourhood, virtual maze)

Virtual reality task NC (n = 30) miAD (n = 20) aMCImd (n = 30) aMCIsd (n = 30)
Virtual neighbourhood
Mean correct response (5 trials) 4.333  0.711 0.35  0.489* 2.1  0.994*,** 4.133  0.507**,****
Mean response time (s) 77.57  17.156 173.49  9.106* 136.433  20.669*,** 83.33  12.793**,****
Virtual maze
Mean correct response (5 trials) 4.033  0.764 0.15  0.366* 1  0.787*,** 3.9  0.712**,****
Mean response time (s) 95.78  17.971 178.02  4.854* 163.713  12.824*,*** 100.513  16.079**,****

* P < 0.001 compared to the NC group. ** P < 0.001 compared to the miAD group. *** P < 0.005 compared to the miAD group. **** P < 0.001 compared to the
aMCImd group. All comparisons made based on ANOVA with Tukey’s post-hoc test. aMCImd, multiple-domain amnestic mild cognitive impairment; aMCIsd,
single-domain amnestic mild cognitive impairment; miAD, mild Alzheimer’s disease; NC, cognitively normal controls; VRNT, virtual reality navigation task.
Values are mean  SD.

Virtual maze task was found between neuropsychological scores

Comparing the performance of all groups across the
five virtual maze trials showed significant differences
in the response scores (mean correct response,
P < 0.001) and response times (P ≤ 0. 002). Tukey’s
post-hoc test revealed that miAD subjects performed
worse than the NC and aMCI groups on the virtual
maze task (P < 0.001). The response time analysis
for all groups showed that miAD subjects required
more time to complete the trials than the others
(P < 0.001). Also, there was a significant difference
between aMCIsd and aMCImd subjects (P < 0.001).
A comparison of aMCI and NC subjects indicated
that there were no significant differences with regard
response scores or response time (P > 0.05)
(Table 2).
Relationship between neuropsychological
variables and virtual neighbourhood
performance
Pearson’s correlation coefficient was used to deter-
mine the relationship between neuropsychological
parameters and the virtual neighbourhood scores. The
results showed a strong positive correlation between
neuropsychological and virtual neighbourhood scores
in all groups (P < 0.01). A strong negative correlation
(RAVLT total scores, immediate recall, and delayed
recall; R-OCFT immediate and delayed recall) and the
mean response time for the virtual neighbourhood task
(P < 0.01) (Table 3).
Relationship between neuropsychological
variables and virtual maze performance
A strong positive relationship was seen between all
neuropsychological scores and virtual maze scores
(P < 0.001). However, the relationship between neu-
ropsychological scores and the mean virtual maze
response time showed a strong negative correlation
in all groups (P < 0.001) (Table 3).
DISCUSSION
The primary aim of this study was to use virtual reality
to compare the allocentric and egocentric memory of
miAD, aMCIsd, aMCImd, and NC subjects. This inves-
tigation revealed significant differences in the allo-
centric and egocentric memory impairments among
miAD and aMCI subtypes. The miAD and aMCImd
subjects were impaired based on the results of the vir-
tual neighbourhood (allocentric memory) and virtual
maze (egocentric memory) tasks; the aMCIsd and NC

Table 3 Correlation between neuropsychological characteristics and the VRNT scores

Mean response time of Mean response
Test Virtual neighbourhood virtual neighbourhood Virtual maze time of virtual maze
RAVLT
Five trials 0.830† −0.846† 0.784† −0.794†
Immediate recall 0.801† −0.822† 0.753† −0.761†
Delayed recall 0.733† −0.795† 0.725† −0.734†
R-OCFT
Immediate recall 0.885† −0.902† 0.847† −0.849†
Delayed recall 0.886† −0.904† 0.860† −0.864†
†
Correlation is significant at the 0.01 level (two-tailed). R-OCFT, Rey-Osterrieth Complex Figure Test; RAVLT, Rey Auditory-Verbal Learning Test; VRNT, virtual
reality navigation task. Values are mean  SD.

6 © 2018 Japanese Psychogeriatric Society


groups performed similarly on both tasks. The aMCIsd
and aMCImd groups performed significantly better on
finding the target and required less time in the virtual
environment than the aMCImd and miAD groups,
respectively. Comparisons of the time spent to find
the goal in the virtual maze and the virtual neighbour-
hood showed that subjects needed more time to find
the goal in the virtual maze than in the virtual neigh-
bourhood. The miAD group spent the most time find-
ing the goal, whereas the NC group spent the least
time. In addition, the aMCI subtypes had more diffi-
culty finding their route in the virtual maze than in the
virtual neighbourhood. In the other words, our findings
indicated that the aMCIsd, aMCImd, and miAD sub-
jects were more impaired in their egocentric than allo-
centric orientation. The aMCIsd subjects did not
perform as well as the NC subjects, but the difference
was not significant either in allocentric or egocentric
memory; this suggests that aMCIsd subjects cannot
be distinguished from NC subjects via VRNT. How-
ever, aMCIsd subjects performed significantly better
than the aMCImd and miAD subjects and can be eas-
ily distinguished from them.
In line with Hort et al.,36 who reported similarities
in spatial navigation between aMCImd and miAD
patients,36 we hypothesized that miAD and aMCImd
subjects may be more impaired than aMCIsd sub-
jects in the virtual neighbourhood and virtual maze.
This hypothesis was supported by our results: miAD
and aMCImd subjects were impaired in both the vir-
tual neighbourhood (allocentric memory) and virtual
maze (egocentric memory) tasks, but aMCIsd sub-
jects performed similarly to the NC subjects on both
tasks. The differences between the aMCIsd and
aMCImd groups were significant, but those between
the aMCIsd and NC groups were not. Our findings
also indicated that the miAD and aMCImd groups
were more impaired than the others with regard to
finding their way in the virtual environments; specifi-
cally, they could not find landmarks and took a long
time to reach the goal (parking in the virtual neigh-
bourhood; finding the ball in the virtual maze).
Although only one previous study has addressed
allocentric and egocentric memory deficits based on
distinctions in aMCIsd and aMCImd,36 several stud-
ies have examined these deficits among aMCI and
AD subjects. Previous reports considered allocentric
or/and egocentric navigation deficits in patients with
MCI, aMCI (without single- or multiple-domain
© 2018 Japanese Psychogeriatric Society
Multiple- but not single-domain aMCI
classification), and early AD in real or virtual environ-
ments.21,35,37,41,43,44,53 Kalová et al. reported that
subjects with early-stage AD were severely impaired
only in allocentric navigation and were able to
remember several locations, but patients with subjec-
tive memory problems showed no impairment.43
Kalová et al. used HGT for the first time, and their
results were similar in both real and computer ver-
sions.43 A case study, Burgess et al. reported a dis-
tinct allocentric spatial memory deficit in a patient
with very early AD.53 deIpolyi et al. and Cushman
et al. reported that patients with mild and/or early-
stage AD or MCI were impaired in recalling previously
learned routes and landmarks; however, neither study
classified the domains of the MCI patients or distin-
guished between egocentric and allocentric
navigation.21,41
In another study, Laczó et al. demonstrated that
hippocampal aMCI subjects were more impaired than
non-hippocampal aMCI subjects in spatial naviga-
tion, but they did not categorize subjects as having
aMCIsd or aMCImd.44 Likewise, Weniger et al. com-
pared the egocentric and allocentric memory deficits
of 29 patients with aMCI (without domain categoriza-
tion) with 29 healthy matched controls using a virtual
reality environment (similar to our VRNT) that was
superior to previously designed tasks.35 They
reported allocentric and egocentric spatial navigation
deficits, in addition to reduced right/left hippocampal
volumes, in aMCI patients relative to cognitively
healthy controls.35 Hort et al. found that patients with
aMCImd and AD were impaired in both allocentric
and egocentric navigation compared to healthy con-
trols, whereas aMCIsd patients were impaired only in
the allocentric navigation.36 Also, Hort et al. reported
that aMCIsd group performed 1.5-fold worse than
the control group.36
In line with the report by Hort et al., our results
showed that the miAD and aMCImd subjects were
impaired in both allocentric (virtual neighbourhood)
and egocentric (virtual maze) navigation, but the
aMCImd subjects performed significantly better than
miAD subjects. Unlike that report, we did not find that
aMCIsd subjects had significantly impaired allo-
centric navigation; in fact, we found that the aMCIsd
group performed similarly to the NC group in allo-
centric and egocentric navigation. Our findings indi-
cated that the aMCIsd subjects, as well as the
aMCImd and miAD subjects, were more impaired in
7
A. Mohammadi et al.
egocentric than allocentric orientation (Table 2), sug-
gesting that egocentric memory may be a potential
biomarker (along with other neuropsychological
assessments) to identify these patients. These valua-
ble results may be thanks to the accuracy and com-
prehensiveness of our newly developed VRNT.
We also explored the performance of the miAD,
aMCIsd, and aMCImd subjects on the RAVLT and
compared them with those of NC subjects. The
results showed that miAD, aMCImd, and aMCIsd
subjects performed worse on the RAVLT than the
aMCImd, aMCIsd, and NC subjects, respectively.
Unlike on the VRNT, aMCIsd subjects performed sig-
nificantly worse than NC subjects on the RAVLT,
suggesting that the RAVLT can be used as a subsidi-
ary psychological task to distinguish MCI subtype
from normal elderly subjects.
Auditory-verbal memory is routinely assessed by
RAVLT in MCI and AD patients, and their perfor-
mance is compared with healthy subjects. It has
been shown that the RAVLT subtests are reliable
tools for distinguishing old-old individuals from AD
patients. Furthermore, performance on the RAVLT
delayed recall can differentiate individuals in the
prodromal phase of AD and MCI from each other and
from the healthy individuals.54,55 Similarly, Tierney
et al. demonstrated that the RAVLT delayed recall
can help predict probable AD with a high degree of
accuracy.56 Our study also revealed that delayed
recall contributes to the early detection of miAD
patients and the differentiation of aMCI subtypes
from cognitively normal subjects. Our findings con-
firmed that the RAVLT can help predict probable
aMCI, and we suggest that this test be used in the
early assessment of individuals with subjective mem-
ory complaints.
In this study, we analyzed the relationship between
performance on the RAVLT subtests and on the
VRNT. Our analysis showed that there is a strong
positive relationship between the RAVLT total score,
immediate recall, and delayed recall and the number
of correct responses in the virtual neighbourhood
and the virtual maze. A strong negative relationship
was observed between the performances on the
RAVLT subtests and the spent time to find the given
goal in the both virtual neighbourhood and the
virtual maze.
Several studies have reported a reduction in the
volume of the hippocampus and some brain regions,
8 © 2018 Japanese Psychogeriatric Society
such as parahippocampal and cingulate cortex, in
patients with AD and MCI.35,57–62 It was reported that
performance on a virtual navigation task is confi-
dently associated with the grey matter volume of the
hippocampus and that MCI subjects with hippocam-
pal memory impairment have many problems in
either allocentric or egocentric navigation.22,44,63,64
Also, the allocentric navigation performance of aMCI
and AD patients has been associated with the grey
matter volume of the dorsolateral prefrontal cortex
and right hippocampus.21,23 It is believed that the
posterior hippocampus and posterior parietal cortex
are brain regions that degenerate during the early
stages of AD.65–67 Correct route learning and spatial
abilities in MCI and AD patients are positively corre-
lated with the volumes of these regions.21 A recent
functional MRI study showed that the bilateral activity
of the most posterior medial temporal lobe, precu-
neus, postcentral gyrus, and retrosplenial cortex
(noticeable on the right side) increased while sub-
jected learned the virtual maze.68 Therefore, analyz-
ing spatial disorientation (allocentric and egocentric
navigation deficits), RAVLT scores, and functional
MRI scans of the hippocampus, posterior parietal
cortex, precuneus, postcentral gyrus, and retrosple-
nial cortex can useful in determining a specific pat-
tern that identifies aMCIsd, aMCImd, and miAD and
preventing aMCIsd from developing into aMCImd
and subsequently miAD.
We concluded that miAD and aMCImd subjects
demonstrated impaired egocentric, allocentric, visual,
and verbal memory in performing the VRNT tasks,
but their allocentric memory was better than their
egocentric memory (Table 4). The current study
documented important differences between the per-
formance of miAD, aMCIsd, aMCImd, and NC sub-
jects based on VRNT and RAVLT. These findings
suggest that aMCImd patients, but not aMCIsd
patients, are detectable from normal elderly subjects
by VRNT; this test, along with the RAVLT and R-
OCFT, can be used as a valid neuropsychological
biomarker to properly distinguish these patients from
each other. Ultimately, simultaneous use of functional
MRI, VRNT, RAVLT, and other diagnostic techniques
may be very useful in obtaining an accurate
diagnosis.
The main limitation of the present study was the
low number of aMCIsd and aMCImd subjects and
the difficulty in finding them. The second limitation of
 Multiple- but not single-domain aMCI

Table 4 Spatial disorientation and visual/verbal memory deficits in the aMCIsd, aMCImd, and miAD patients
Patients Allocentric Egocentric Verbal memory Visual memory
†,‡,§ †,‡,§ †,‡,§
miAD Impaired Impaired Impaired Impaired†,‡,§
Lowest performance among all Lowest performance Worst performance among Worst performance among
subjects among all subjects subjects subjects
Getting lost and confused in Getting lost (too often) and Lower than other groups Lower than other groups
navigation confused in navigation
Better than egocentric navigation Worse than allocentric
navigation
aMCImd Impaired†,‡,¶ Impaired†,‡,¶ Impaired†,‡,¶ Impaired†,‡,¶
Better performance than miAD, Better performance than Better performance than Better performance than
but significantly worse than NC miAD, but worse than miAD, but worse than miAD, but worse than
and aMCIsd subjects aMCIsd and NC aMCIsd and NC aMCIsd and NC
subjects subjects subjects
Getting lost and confused in Worse than allocentric
navigation, but less so than navigation
miAD subjects
More confused than in
allocentric navigation
aMCIsd Almost not impaired¶,††,‡‡ Almost not impaired¶,††,‡‡ Almost not impaired†,¶,†† Almost not impaired†,¶,††
Performed similar to NC Performed similar to NC Significantly worse than Significantly worse than
NC, but significantly NC, but significantly
better than miAD and better than miAD and
aMCImd aMCImd
Slightly worse than NC, but not Slightly worse than NC,
significant but not significant
Significantly better than miAD Significantly better than
and aMCImd miAD and aMCImd
Slight confusion in navigation Lower than allocentric
navigation
†
Significantly worse than NC subjects (P < 0.001). ‡ Significantly worse than aMCIsd subjects (P < 0.001). § Significantly worse than aMCImd subjects
(P < 0.001). ¶ Significantly worse than miAD subjects (P < 0.001). †† Significantly better than aMCImd subjects (P < 0.001). ‡‡ Slightly worse than NC, but not sig-
nificant. aMCImd, multiple-domain amnestic mild cognitive impairment; aMCIsd, single-domain amnestic mild cognitive impairment; miAD, mild Alzheimer’s
disease; NC, cognitively normal controls.

this study was the unwillingness of some subjects to
simultaneously perform the VRNT and complete the
RAVLT and R-OCFT with MRI during the second
phase of this project.
ACKNOWLEDGMENTS
This research was supported by a grant from the
Neuroscience Research Center, Baqiyatallah Univer-
sity of Medical Sciences (grant no. BMSU/950896).
We thank the subjects who participated in this study.
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