MINI REVIEW ARTICLE
published: 21 June 2012
Spatial navigation—a unique window into physiological
and pathological aging
Ivana Gazova1,2*, Kamil Vlcek2,3, Jan Laczó1,2, Zuzana Nedelska1,2, Eva Hyncicova1, Ivana Mokrisova1,
Katerina Sheardova2and Jakub Hort1,2
1Department of Neurology, Memory Disorders Clinic, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague 5,
2International Clinical Research Center and St. Anne’s University Hospital Brno, Brno, Czech Republic
3Department of Neurophysiology of Memory, Institute of Physiology Academy of Sciences of the Czech Republic v.v.i., Prague, Czech Republic
Thomas Wolbers, University of
Jacques Micheau, University of
Bordeaux 1, France
Jose-Vicente Lafuente, University
of Basque Country, Spain
Ivana Gazova, Department of
Neurology, Memory Disorders
Clinic, 2nd Faculty of Medicine,
Charles University in Prague and
University Hospital Motol,
V Uvalu 84, Prague 5, 150 06,
Spatial navigation is a skill of determining and maintaining a trajectory from one place to
another. Mildprogressive declineof spatialnavigation develops graduallyduring the course
of physiological ageing. Nevertheless, severe spatial navigation deficit can be the first sign
of incipient Alzheimer’s disease (AD), occurring in the stage of mild cognitive impairment
(MCI), preceding the development of a full blown dementia. Patients with amnestic MCI,
especially those with the hippocampal type of amnestic syndrome, are at very high risk of
AD. These patients present with the same pattern of spatial navigation impairment as do
the patients with mild AD. Spatial navigation testing of elderly as well as computer tests
developed for routine clinical use thus represents a possibility for further investigation of
this cognitive domain, but most of all, an opportunity for making early diagnosis of AD.
Keywords: spatial navigation, physiological ageing, pathological ageing, mild cognitive impairment, Alzheimer’s
disease, allocentric navigation, egocentric navigation
Spatial navigationis the abilityto determine andmaintain aroute
from one place to another (Gallistel, 1990). It consists of phylo-
genetically old cognitive functions allowing animals and humans
to remember important locations and their mutual relations as
well as their relation to the organism itself. Spatial navigation
deficits are frequently observed inolder populationwith a signifi-
cant influence on the quality of life. Spatial navigation difficulties
can represent the first sign of Alzheimer’s disease (AD) develop-
ment. The recent trend of spatial navigation research relies on
tests translated from animal experiments, e.g., the human analog
of the Morris Water Maze (MWM), used for clinical examina-
tion of people at risk of AD. In this article we summarize findings
on spatial navigation changes in the physiological and patholog-
ical ageing and their practical significance for the early diagnosis
of AD. As many neuropsychological tools still evoke controver-
sies regarding the accuracy of detecting AD in its predementia
stages, it is important to designa battery oftests, including spatial
navigation testing for improving early diagnosis of AD.
PHYSIOLOGICAL AND PATHOLOGICAL AGEING
Physiological ageing is associated with structural and functional
changes, mainly in the prefrontal cortex (Cabeza et al., 1997;
Resnick et al., 2003) and to a lesser extent in the hippocam-
pus (Jack et al., 1998; Grady et al., 1999), these are mirrored by
changes in cognitive functions. Age-related changes in cognition
include mild decline in attention, executive functions, working
memory, and free memory recall, while other functions such as
visuospatial functions, language, and semantic memory remain
generally preserved for a long time (Park, 2000).
Pathological ageing is caused by underlying vascular or neu-
rodegenerative diseases leading gradually to a dementia syn-
drome, where AD is the most common cause. The hallmark of
AD is medial temporal lobe (MTL) atrophy including the hip-
pocampus and the enthorinal cortex (Jack et al., 1997). Some
recent studies on patients with AD suggested that atrophy is
unequally distributed even within the hippocampus being most
pronounced in the CA1 subfield compared to hippocampal atro-
phy pattern in normal ageing, where the CA1 subfield is relatively
spared (Frisoni et al., 2008; Mueller and Weiner, 2009). The CA1
atrophy in patients with mild cognitive impairment (MCI) can
even predict conversion to dementia due to AD (Chételat et al.,
2008; Devanand et al., 2012). Besides the MTL structures, the
precuneus was shown to be impaired very early even in presymp-
tomatic AD (Scahill et al., 2002). With the disease progression,
structures beyond MTL including lateral temporal, parietal and
frontal cortices become affected (Braak and Braak, 1991). The
first clinical sign of AD is usually the insidious onset of episodic
memory impairment caused by neuropathological changes in
MTL. Early in the course of the disease, memory impairment
is followed by executive dysfunction together with impairment
of working memory and attention. Later on, other cognitive
domains including praxis, visuo-constructive skills, and language
become affected, which reflects the spreading of the pathology
further to the neocortex (Kertesz et al., 1986; Baudic et al., 2006).
Proceeding cognitive impairment leads to a decline in every day
functional abilities, which constitutes an important criterion for
the diagnosis of the dementia syndrome.
In recent years, increasing attention has been paid to the
mild end of the cognitive spectrum encompassing a transient
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Gazova et al. Spatial navigation in aging
zone between the normal ageing and dementia, caused most fre-
quently by AD. This transitional zone has been described by the
term MCI (Petersen et al., 1999). The concept of MCI refers
to a group of individuals who have some cognitive impairment
yet of insufficient severity to constitute dementia due to a very
form a heterogeneous group. Those with memory impairment
(amnesia) present amnestic MCI (aMCI), those with the non-
memory domain impairment (i.e., executive functions, language,
and visuo-spatial skills) present non-amnestic MCI (naMCI)
(Petersen et al., 2001). Further sub-classification of both MCI
subtypes is based on the number of affected cognitive domains.
Isolated memory impairment represents aMCI single domain
(aMCIsd), similarly, single non-memory domain impairment
represents naMCI single domain (naMCIsd). Impairment in
additional domains to these two subtypes assigns to aMCI multi-
ple domain(aMCImd), or naMCI multiple domain (naMCImd).
Individuals with aMCI subtype have a high risk of AD develop-
ment; while those with naMCI subtype have a higher probability
of progressing to non-AD dementias such as dementia with Lewy
bodies, frontotemporal orvasculardementia. The riskofprogres-
sion from MCI to dementia, particularly to AD, is not uniform
and varies across epidemiological studies (Tierney et al., 1996;
Petersen et al., 1999; Morris et al., 2001). The average rate of con-
version is estimated to 12% per year (Petersen and Morris, 2003).
In contrast, in healthy elderly subjects the rate of conversion to
dementia is about 1–2% per year (Petersen et al., 1999).
Although aMCI patients represent at-risk population for AD
development, this population is somewhat heterogeneous as it
encompasses also individuals who will never progress to demen-
tia. Lately, much effort is spent to identify the high risk patients
with underlying AD pathology already in this prodromal (pre-
dementia) stage of the disease. For identification of prodromal
AD patients, a combination of neuropsychological tests with
various biomarkers is used. These include structural and func-
tional neuroimaging, focused on the hippocampus and related
structures (Small et al., 1999; Visser et al., 1999; Desikan et al.,
2010), magnetic resonance spectroscopy (Modrego et al., 2011),
cerebrospinal fluid assessment of amyloid-β peptide, tau and
phosphorylated tau proteins (Hulstaert et al., 1999; Shaw et al.,
2009), and amyloid labeling PET ligands (Resnick et al., 2010).
Among neuropsychological tools, specific memory tests play an
important role for identification of memory profile character-
istic for AD that is present already in the predementia stages
(Sarazin et al., 2007)—“amnestic syndrome of the hippocam-
pal type” (Dubois and Albert, 2004). This syndrome forms a
clinical core of the revised research diagnostic criteria for AD
(Dubois et al., 2007) and is characterized by decreased mem-
ory recall despite controlled encoding and using of facilitation
retrieval techniques (cueing or recognition) (Dubois, 2000). The
MCI individuals with amnestic syndrome of the hippocampal
type (HaMCI), compared to those with the amnestic syndrome
of the non-hippocampal type (NHaMCI), form the major at-
risk subgroup of MCI population (Sarazin et al., 2007) for the
development of dementia due to AD. Although the tests designed
to detect hippocampal amnestic syndrome (Grober et al., 1988)
were shown to reflect atrophy of the hippocampus, especially its
CA1 subfield (Sarazin et al., 2010), it still remains controversial,
whether these tests are superior to other tests for the detection of
early stage dementia (de Jager et al., 2010; Carlesimo et al., 2011).
Theuncertainty abouttheusefulness ofcuedrecallasadiagnostic
tool for MCI andAD is expressed also inthe National Institute on
Aging and the Alzheimer’s Association guidelines (Albert et al.,
2011; McKhann et al., 2011), which take into account symptoms
of patients with predominant parietal atrophy.
Recent studies indicate that there is a promising chance that,
spatial navigation tests reflecting MTL damage may identify
patients with AD already in the prodromal stages (Laczó et al.,
SPATIAL NAVIGATION STRATEGIES AND ITS
While navigating through the environment, people can use two
basic navigation strategies associated with distinct internal rep-
resentations of space. The egocentric navigation is body-centered
strategy that utilizes distances and directions to or from individ-
ual landmarks with respect to the subject’s body position. The
allocentric navigation is a world-centered strategy using informa-
tion about distances and angles between different locations in the
environment independent of the position of the subject.
Animal research yielded valuable information about the role
of MTL in the processes of spatial navigation (O’Keefe and
Dostrovsky, 1971; O’Keefe and Nadel, 1978; Morris et al., 1982).
A key structure of the allocentric navigation is the hippocampus,
Dostrovsky discovered specific place-firing cells in the hippocam-
pus of the rat (O’Keefe and Dostrovsky, 1971). These findings
supported the theory of a cognitive map (Tolman, 1948) and the
dissociation between the egocentric and allocentric navigation
strategies. Experiments in the MWM demonstrated spatial nav-
igation impairment in the rats after hippocampal lesion (Morris
et al., 1982). Hippocampus is crucial for consolidation, encod-
ing, and long term storage of spatial information (Squire, 1992).
The association of hippocampus with allocentric navigation in
humans has been demonstrated in various studies in real-space
In one study, Holdstock et al. (2000) tested patient (YR) with
selective bilateral hippocampal lesion for recall of visuospatial
information and found that YR was more impaired at recalling
allocentric than egocentric information. More specifically, right
CA1 hippocampal subfield seems to be involved in encoding of
allocentric spatial information in humans (Suthana et al., 2009).
There is evidence that egocentric information is processed out-
side of the hippocampal system (O’Keefe and Nadel, 1978), in
the parietal cortex including precuneus and the caudate nucleus
(Mountcastle et al., 1975; Maguire et al., 1998). Lesions of the
right posterior parietal cortex are characterized by an egocentric
orientation deficit (Kase et al., 1977; Levine et al., 1985; Stark
et al., 1996).
SPATIAL NAVIGATION IMPAIRMENT IN PHYSIOLOGICAL
AND PATHOLOGICAL AGEING
Spatial navigation has been thoroughly studied in animal models.
Navigational tasks based on the models of MWM (Morris, 1981)
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Gazova et al. Spatial navigation in aging
were used in testing rats of different age (Ingram, 1988; McLay
et al., 1999; Begega et al., 2001). Results of these studies suggested
age-related deficit of navigational abilities in aged rodents and
inspired translational research of spatial navigation in humans.
Studies in different environments compared healthy elderly per-
sons with younger adults. Significant deficits in learning a route
through a hospital lobby was described in participants 60 years
and older, with a tendency to be impaired even in participants
in their 50s (Barrash, 1994). Several studies suggested that elderly
cessing. In one experiment using series of slides of unfamiliar
neighborhood, elderly adults recalled landmarks by their saliency
and non-spatial associations rather than by their spatial relation-
ships (Lipman, 1991). However, many other studies emphasized
deficits specifically in spatial configuration memory and in place
navigation in aged population. Wilkniss et al. (1997) let par-
ticipants undergo navigational tasks in university building and
found that older persons made more errors than their younger
counterparts in temporal ordering of landmarks, in recalling the
learned route, and in using the learned map in navigation. These
deficits suggest a lower abilityto use a configural spatial represen-
tation to navigate. Another study showed navigational difficulties
ofhealthy elderlywhiledriving acarleading to avoidanceofunfa-
miliar places and routes and thus limiting their mobility (Burns,
1999). Human analog of the MWM was developed in an effort
to transform navigational tasks into laboratory conditions. It was
and use of the cognitive map of the maze in the group of elderly
participants (Newman and Kaszniak, 2000). Moffat and Resnick
(2002) were among the first authors implementing the use of vir-
tualrealityintesting ofspatialnavigation. Theycomparedperfor-
mance of elderly and younger individuals in the virtual analog of
MWM and found deficit of place learning using room-geometry
cues in the group of older participants. Furthermore, they sug-
gested that allocentric impairment may contribute to age-related
deficit of spatial navigation. This hypothesis was later supported
by the study of Iaria and colleagues, according to which the older
participants are less effective in forming and using the cognitive
maps of an environment (Iaria et al., 2009). A recent study exam-
ined age-related differences in strategy preference and found a
shift toward egocentric navigation strategy in older participants,
which may reflect an adaptation mechanism for the hippocampal
dysfunction (Rodgers et al., 2012). Studies correlating hippocam-
pal volume with spatial navigation performance in cognitively
of them documenting positive correlation (Driscoll et al., 2003;
Head andIsom,2010)andother reporting noassociation(Moffat
et al., 2006; Nedelska et al., 2012).
Spatial navigation impairment occurs early in AD (Monacelli
et al., 2003; Pai and Jacobs, 2004); reports about spatial deficits
such as getting lost in familiar places and other can in many
cases lead to diagnosis of dementia (Klein et al., 1999). The com-
bination of visual perception and memory deficits is probably
the mostly defining factor of spatial disorientation in patients
with AD (Henderson et al., 1989), where both allocentric and
egocentric navigation strategies are impaired (Hort et al., 2007;
Weniger et al., 2011). According to several studies, these general
spatial deficits in AD seem to be linked mainly to impairment
of visual motion processing (Kavcic et al., 2006). Nevertheless,
spatial navigation impairment can be detected even before the
development of the full blown dementia syndrome, in the stage
of MCI (Mapstone et al., 2003; deIpolyi et al., 2007; Hort et al.,
2007; Laczó et al., 2011). Given that aMCI is associated with a
higher risk of progression to AD, the current research of spatial
navigation has focused on this group of patients. A visuospa-
tial subtype of aMCI with impaired radial motion perception
indicating spatial perception deficit was identified in one of the
first studies in this field (Mapstone et al., 2003). Spatial naviga-
tion impairment was documented in aMCI patients performing
a route-learning task in the hospital lobby (deIpolyi et al., 2007).
In this study, the patients, who made at least one error on the
road, did not differ in neuropsychological tests from those with
parietal cortex volumes that probably underlie spatial navigation
deficit. Temporal order spatial memory was recently suggested as
Remembering a sequence of three turns in a simple maze distin-
guished well between AD, healthy older subjects, and group of
patients with frontotemporal lobe degeneration. Spatial naviga-
tion impairment is present evenin patients with isolated memory
deficit aMCIsd (Hort et al., 2007). The patients with aMCIsd
tested in the real-space human version of the MWM had an
isolated impairment of allocentric navigation, suggesting spa-
tial memory impairment due to MTL dysfunction. On the other
hand, the patients with aMCImd had more general spatial navi-
gation impairment in both, allocentric and egocentric strategies,
indicating that structures beyond MTL, presumably the parietal
cortex, are affected in this group (Hort et al., 2007). Consistent
with these findings patients with aMCI were impaired in both
egocentric and allocentric strategies in a study using virtual real-
ity environment, where right precuneus volume was associated
with egocentric navigation performance (Weniger et al., 2011).
Further study examined spatial navigation in a real-space human
version of MWM and found more profound spatial navigation
especially in allocentric navigation, which corresponds with the
probable hippocampal dysfunction (Laczó et al., 2009). In addi-
tion, the HaMCI group resembled the AD group in spatial navi-
gation performance thus indicating that spatial navigation deficit
in the HaMCI may be the first sign of incipient AD. In the same
vein, in another study using real-space human analogy of MWM
(Nedelska et al., 2012), right hippocampal volume in aMCI and
AD patients was associated with an allocentric navigation per-
formance. Thus testing of the allocentric navigation, targeting
hippocampus and its CA1 subfield (Suthana et al., 2009), and
egocentric navigation, focusing more on posterior parietal cor-
tex and precuneus, could be a useful method of recognizing the
aMCI patients at higher risk of AD.
Virtual analogs can probably substitute the real space envi-
ronment in estimating the navigational deficits of MCI and AD
patients, as implied by two recent studies. In an experiment
consisting of learning a route through a hospital lobby and of
a follow-up spatial tests series, strong correlation was found
across all subject groups between the total spatial score from the
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June 2012 | Volume 4 | Article 16 | 3
Gazova et al. Spatial navigation in aging
real hospital lobby and the total score from its virtual analog
(Cushman et al., 2008). Similarly, high correlation was found in
another study between scores in a real-space human version of
MWM and its virtual 2D analog on a computer monitor repre-
results suggest that computer analogs of real space tests can yield
measures of broad applicability to early detection of navigational
impairment in MCI or AD.
In the course of physiological ageing, there is a selective mild
decline of spatial navigation. Particularly allocentric navigation
is impaired, which may be a consequence of the age-related
deficits in mediotemporal functioning observed in the elderly.
AD is associated with the development of characteristic patho-
logical changes in the brain, especially in the hippocampus and
its CA1 subfield, that further spread to parietal cortex, including
precuneus, and other areas as the disease progresses. The severe
spatial navigation deficits demonstrated in patients in early stage
of AD are caused by both hippocampal and parietal dysfunc-
tion. Those spatial navigation deficits can be detected even in the
stage of MCI patients with amnestic syndrome of hippocampal
types, who are at the highest risk of AD development, and who
manifest with the spatial navigation deficit similar to that in AD.
Therefore, spatial navigation testing could become a reliable tool
of identifying patients in the prodromal stages of AD, before the
navigation tests to neuropsychological batteries will increase the
diagnostic accuracyandearlydetection ofpatients withAD inthe
ficult, new methods of testing are being developed. 2D computer
tests and virtual reality environments appear to be promising
areas for extension of spatial navigation testing to the routine
This work was supported by Grant Agency of the Czech
Republic Grants 309/09/1053 and 309/09/0286; European
CZ.1.05/1.1.00/02.0123); Internal Grant Agency of the Ministry
of Health of the Czech Republic Grant NT11225-4; Ministry
of Education, Youth and Sports of the Czech Republic Grants
1M0517 and LC554, and research project AV0Z50110509, Grant
Agency of Charles University in Prague (No. 2120145) and
Institutional Support of Laboratory Research Grant No. 2/2012
Albert, M. S., DeKosky, S. T., Dickson,
D., Dubois, B., Feldman, H. H., Fox,
N. C., Gamst, A., Holtzman, D. M.,
Jagust, W. J., Petersen, R. C., Snyder,
P. J., Carrillo, M. C., Thies, B., and
Phelps, C. H. (2011). The diagnosis
of mild cognitive impairment due
to Alzheimer’s disease: recommen-
dations from the National Institute
on Aging-Alzheimer’s Association
workgroups on diagnostic guide-
Alzheimers Dement. 7, 270–279.
Astur, R. S., Taylor, L. B., Mamelak, A.
(2002). Humans with hippocampus
damage display severe spatial mem-
ory impairments in a virtual Morris
water task. Behav. Brain Res. 132,
Barrash, J. (1994). Age-related decline
Neuropsychol. 10, 189–201.
Baudic, S., Barba, G. D., Thibaudet,
M. C., Smagghe, A., Remy, P., and
Traykov, L. (2006). Executive func-
tion deficits in early Alzheimer’s
disease and their relations with
Neuropsychol. 21, 15–21.
Begega, A., Cienfuegos, S., Rubio, S.,
Santín, J. L., Miranda, R., and Arias,
J. L. (2001). Effects of ageing on
allocentric and egocentric spatial
strategies in the Wistar rat. Behav.
Processes 53, 75–85.
Bellassen, V., Iglói, K., de Souza, L.
C., Dubois, B., and Rondi-Reig,
L. (2012). Temporal order memory
assessed duringspatiotemporal nav-
igation as a behavioral cognitive
marker for differential Alzheimer’s
disease diagnosis. J. Neurosci. 32,
Braak, H., and Braak, E. (1991).
Neuropathol. 82, 239–259.
Brun, V. H., Leutgeb, S., Wu, H. Q.,
Schwarcz, R., Witter, M. P., Moser,
E. I., and Moser, M. B. (2008).
Impaired spatial representation in
CA1 after lesion of direct input
from entorhinal cortex. Neuron 57,
Burns, P. C. (1999). Navigation and the
B Psychol. Sci. Soc. Sci. 54, 49–55.
Cabeza, R., Grady, C. L., Nyberg, L.,
McIntosh, A. R., Tulving, E., Kapur,
S., Jennings, J. M., Houle, S., and
Craik, F. I. (1997). Age-related dif-
ferences in neural activity during
memory encoding and retrieval:
a positron emission tomography
study. J. Neurosci. 17, 391–400.
Caltagirone, C. (2011). Category
cued recall following controlled
encoding as a neuropsychological
tool in the diagnosis of Alzheimer’s
disease: a review of the evidence.
Neuropsychol. Rev. 21, 54–65.
Chételat, G., Fouquet, M., Kalpouzos,
G., Denghien, I., De la Sayette, V.,
Viader, F., Mézenge, F., Landeau,
B., Baron, J. C., Eustache, F., and
Perri, R., and
dimensional surface mapping of
hippocampal atrophy progression
from MCI to AD and over normal
aging as assessed using voxel-based
morphometry. Neuropsychologia 46,
Cushman, L. A., Stein, K., and Duffy,
C. J. (2008). Detecting naviga-
tional deficits in cognitive aging and
Alzheimer disease using virtualreal-
ity. Neurology 71, 888–895.
Miller, B. L., and Gorno-Tempini,
M. L. (2007). Spatial cognition
and the human navigation network
in AD and MCI. Neurology 69,
evaluation of revised criteria for
the diagnosis of Alzheimer’s disease
using a cohort with post-mortem
diagnosis. Int. J. Geriatr. Psychiatry
Desikan, R. S., Sabuncu, M. R.,
Cabral, H. J., Hess, C. P., Weiner,
M. W., Biffi, A., Anderson, C. D.,
Rosand, J., Salat, D. H., Kemper,
T. L., Dale, A. M., Sperling, R. A.,
and Fischl, B. (2010). Alzheimer’s
Selective disruption of the cerebral
neocortex in Alzheimer’s disease.
PLoS ONE 5:e12853. doi: 10.1371/
Devanand, D. P., Bansal, R., Liu,
J., Hao, X., Pradhaban, G., and
Peterson, B. S. (2012). MRI hip-
pocampal and entorhinal cortex
Alzheimer’s disease. Neuroimage 60,
Brooks, W. M., Baumgartner, R.
N., and Sutherland, R. J. (2003).
The aging hippocampus: cognitive,
biochemical andstructural findings.
Cereb. Cortex 13, 1344–1351.
useful concept than mild cognitive
impairment? Curr. Opin. Neurol. 13,
Dubois, B., and Albert, M. L. (2004).
Alzheimer’s disease? Lancet Neurol.
Dubois, B., Feldman, H. H., Jacova, C.,
Dekosky, S. T., Barberger-Gateau,
P., Cummings, J., Delacourte, A.,
Galasko, D., Gauthier, S., Jicha, G.,
Meguro, K., O’brien, J., Pasquier,
F., Robert, P., Rossor, M., Salloway,
S., Stern, Y., Visser, P. J., and
Scheltens, P. (2007). Research crite-
ria for the diagnosis of Alzheimer’s
ADRDA criteria. Lancet Neurol. 6,
Frisoni, G. B., Ganzola, R., Canu, E.,
Rüb, U., Pizzini, F. B., Alessandrini,
F., Zoccatelli, G., Beltramello, A.,
Caltagirone, C., and Thompson,
P. M. (2008). Mapping local hip-
pocampal changes in Alzheimer’s
Frontiers in Aging Neurosciencewww.frontiersin.org
June 2012 | Volume 4 | Article 16 | 4
Gazova et al. Spatial navigation in aging
at 3 Tesla. Brain 131, 3266–3276.
Gallistel, C. R. (1990). The Orga-
nization of Learning. Cambridge,
MA: MIT Press.
Grady,C. L.,McIntosh, A.R., Rajah, M.
N., Beig, S., and Craik, F. I. (1999).
The effects of age on the neural cor-
relates of episodic encoding. Cereb.
Cortex 9, 805–814.
Grober, E., Buschke, H., Crystal, H.,
Bang, S., and Dresner, R. (1988).
Screening for dementia by memory
testing. Neurology 38, 900–903.
Head, D., and Isom, M. (2010). Age
effects on wayfinding and route
Henderson, V. W., Mack, W., and
Williams, B. W. (1989). Spatial dis-
orientation in Alzheimer’s disease.
Arch. Neurol. 46, 391–394.
Holdstock, J. S., Mayes, A. R., Cezayirli,
E., Isaac, C. L., Aggleton, J. P.,
and Roberts, N. (2000). A com-
parison of egocentric and allocen-
tric spatial memory in a patient
with selective hippocampal damage.
Neuropsychologia 38, 410–425.
Hort, J., Laczó, J., Vyhnálek, M.,
Bojar, M., Bures, J., and Vlcek,
K. (2007). Spatial navigation deficit
in amnestic mild cognitive impair-
ment. Proc. Natl. Acad. Sci. U.S.A.
Hulstaert, F., Blennow, K., Ivanoiu,
Riemenschneider, M., De Deyn,
P. P., Bancher,
Wiltfang, J., Mehta, P. D., Iqbal,
K., Pottel, H., Vanmechelen, E.,
Improved discrimination of AD
patients using beta-amyloid(1-42)
and tau levels in CSF. Neurology 52,
Iaria, G., Palermo, L., Committeri, G.,
and Barton, J. (2009). Age differ-
ences in the formation and use of
cognitive maps. Behav. Brain Res.
Ingram, D. K. (1988). Complex maze
learning in rodents as a model
of age-related memory impairment.
Neurobiol. Aging 9, 475–485.
Jack, C. R. Jr., Petersen, R. C., Xu, Y. C.,
O’Brien, P. C., Smith, G. E., Ivnik,
R. J., Tangalos, E. G., and Kokmen,
E. (1998). Rate of medial temporal
lobe atrophy in typical aging and
Alzheimer’s disease. Neurology 51,
Jack, C. R. Jr., Petersen, R. C., Xu, Y.
C., Waring, S. C., O’Brien, P. C.,
Tangalos, E. G., Smith, G. E., Ivnik,
temporal atrophy on MRI in nor-
disease. Neurology 49, 786–794.
Kase, C. S., Troncoso, J. F., Court,
J. E., Tapia, J. F., and Mohr,
J. P. (1977). Global spatial disori-
entation. Clinico-pathologic corre-
lations. J. Neurol. Sci. 34, 267–278.
Kavcic, V., Fernandez, R., Logan,
ceptual correlates of navigational
impairment in Alzheimer’s disease.
Brain 129, 736–746.
Kertesz, A., Appell, J., and Fisman,
M. (1986). The dissolution of lan-
guage in Alzheimer’s disease. Can. J.
Neurol. Sci. 13, 415–418.
Klein, D. A., Steinberg, M., Galik, E.,
Steele, C., Sheppard, J. M., Warren,
A., Rosenblatt, A., and Lyketsos, C.
G. (1999). Wandering behaviour in
community-residing persons with
dementia. Int. J. Geriatr. Psychiatry
Laczó, J., Andel, R., Vlèek, K., Macoška,
V., Vyhnálek, M., Tolar, M., and
Bojar, M. (2011). Spatial navigation
and APOE in amnestic mild cogni-
tive impairment. Neurodegener. Dis.
M., Vlcek, K.,
Gazova, I., Bojar, M., Sheardova, K.,
and Hort, J. (2012). From morris
water maze to computer tests in the
prediction of Alzheimer’s disease.
Neurodegener. Dis. 10, 153–157.
Laczó, J., Vlˇ cek, K., Vyhnálek, M.,
Vajnerová, O., Ort, M., Holmerová,
I., Tolar, M., Andˇ el, R., Bojar, M.,
and Hort, J. (2009). Spatial nav-
igation testing discriminates two
types of amnestic mild cognitive
imairment. Behav. Brain Res. 202,
Levine, D.N., Warach, J.,and Farah, M.
(1985). Two visual systems in men-
tal imagery: dissociation of “what”
and “where” in imagery disorders
due to bilateral posterior cerebral
lesions. Neurology 35, 1010–1018.
Lipman, P. D. (1991). Age and expo-
sure differences in acquisition of
route information. Psychol. Aging 6,
Maguire, E. A., Burgess, N., Donnett,
J. G., Frackowiak, R. S., Frith, C.
D., and O’Keefe, J. (1998). Knowing
where and getting there: a human
navigation network. Science 280,
Mapstone, M., Steffenella, T. M., and
Duffy, C. J. (2003). A visuospatial
variant of mild cognitive impair-
ment: getting lost between aging
and AD. Neurology 60, 802–808.
McKhann, G. M., Knopman, D. S.,
Chertkow, H., Hyman, B. T., Jack,
C. R. Jr., Kawas, C. H., Klunk, W.
E., Koroshetz, W. J., Manly, J. J.,
Mayeux, R., Mohs, R. C., Morris,
J. C., Rossor, M. N., Scheltens,
P., Carrillo, M. C., Thies, B.,
Weintraub, S., and Phelps, C. H.
(2011). The diagnosis of dementia
due to Alzheimer’s disease: rec-
ommendations from the National
Association workgroups on diag-
nostic guidelines for Alzheimer’s
McLay, R. N., Freeman, S. M., Harlan,
R. E., Kastin, A. J., and Zadina,
J. E. (1999). Tests used to assess
the cognitive abilities of aged rats:
their relation to each other and to
hippocampal morphology and neu-
rotrophin expression. Gerontology
Modrego, P. J., Fayed, N., and Sarasa,
M. (2011). Magnetic resonance
spectroscopy in the prediction of
early conversion from amnestic
study. BMJ Open 1, e000007.
Moffat,S. D., Kennedy,
Rodrigue, K. M., and Raz, N.
(2006). Extrahippocampal contri-
butions to age differences in human
spatial navigation. Cereb. Cortex 17,
Effects of age on virtual environ-
ment place navigation and allo-
centric cognitive mapping. Behav.
Neurosci. 116, 851–859.
A., Kavcic, V., and Duffy, C. J.
(2003). Spatial disorientation in
Alzheimer’s disease: the remem-
brance of things passed. Neurology
Morris, G. M. (1981). Spatial local-
ization does not require the pres-
ence of local cues. Learn. Motiv. 12,
Morris, R. G., Garrud, P., Rawlins, J.
N., and O’Keefe, J. (1982). Place
navigation impaired in rats with
hippocampal lesions. Nature 297,
Morris, J. C., Storandt, M., Miller,
J. P., McKeel, D. W., Price, J. L.,
Rubin, E. H., and Berg, L. (2001).
Mild cognitive impairment repre-
sents early-stage Alzheimer disease.
Arch. Neurol. 58, 397–405.
Mountcastle, V. B., Lynch, J. C.,
and Acuna, C. (1975). Posterior
parietal association cortex of the
monkey: command functions for
space. J. Neurophysiol. 38, 871–908.
disease on hippocampal subfields.
Hippocampus 19, 558–564.
Nedelska, Z., Andel, R., Laczó, J.,Vlcek,
K., Horinek, D., Lisy, J., Sheardova,
K., Bures, J., and Hort, J. (2012).
Spatial navigation impairment is
proportional to right hippocampal
volume. Proc. Natl. Acad. Sci. U.S.A.
Newman, M. C., and Kaszniak, A. W.
(2000). Spatial memory and aging:
performance on a human analog of
the Morris water maze task. Aging
Neuropsychol. Cogn. 7, 86–93.
O’Keefe, J., and Dostrovsky, J. (1971).
The hippocampus as a spatial map.
Preliminary evidence from unit
activity in the freely-moving rat.
Brain Res. 34, 171–175.
O’Keefe, J., and Nadel, L. (1978). The
Hippocampus as A Cognitive Map.
Pai, M. C., and Jacobs, W. J. (2004).
community-residing patients with
Alzheimer’s disease. Int. J. Geriatr.
Psychiatry 19, 250–255.
Park, D. C. (2000). “Basic mechanisms
accounting for age-related decline
in cognitive functions,” in Cognitive
Ageing. A Primer, eds D. C. Park
and N. Schwarz (Philadelphia, PA:
Petersen, R. C., Doody, R., Kurz,
A., Mohs, R. C., Morris, J. C.,
Rabins, P.V., Ritchie, K.,Rossor, M.,
Thal, L., and Winblad, B. (2001).
Current concepts in mild cogni-
tive impairment. Arch. Neurol. 58,
“Clinicalfeatures,” inMild Cognitive
Impairment: Aging to Alzheimer’s
Disease, ed. R. C. Petersen (New
York, NY: Oxford University Press,
Petersen, R. C., Smith, G. E., Waring,
S. C., Ivnik, R. J., Tangalos, E. G.,
and Kokmen, E.(1999). Mild cogni-
tive impairment: clinical character-
ization and outcome. Arch. Neurol.
Resnick, S. M., Pham, D. L., Kraut,
M. A., Zonderman, A. B., and
Davatzikos, C. (2003). Longitudinal
magnetic resonance imaging studies
of older adults: a shrinking brain.
J. Neurosci. 23, 3295–3301.
Resnick, S. M., Sojkova, J., Zhou, Y.,
An, Y., Ye, W., Holt, D. P., Dannals,
R. F., Mathis, C. A., Klunk, W.
E., Ferrucci, L., Kraut, M. A., and
Wong, D. F. (2010). Longitudinal
with fibrillar amyloid-beta mea-
sured by [11C]PiB. Neurology 74,
Rodgers, M. K., Sindone, J. A. III., and
Moffat, S. D. (2012). Effects of age
Frontiers in Aging Neuroscience www.frontiersin.org
June 2012 | Volume 4 | Article 16 | 5
Gazova et al. Spatial navigation in aging
on navigation strategy. Neurobiol.
Aging 33, 202.e15–22.
Sarazin, M., Berr, C., De Rotrou, J.,
Fabrigoule, C., Pasquier, F., Legrain,
S., Michel, B., Puel, M., Volteau,
M., Touchon, J., Verny, M., and
Dubois, B. (2007). Amnestic syn-
drome of the medial temporal
type identifies prodromal AD: a
longitudinal study. Neurology 69,
Sarazin, M., Chauviré, V., Gerardin, E.,
Colliot, O., Kinkingnéhun, S., de
Souza, L. C., Hugonot-Diener, L.,
Garnero, L., Lehéricy, S., Chupin,
M., and Dubois, B. (2010). The
amnestic syndrome of hippocam-
pal type in Alzheimer’s disease: an
MRI study. J. Alzheimers Dis. 22,
Scahill, R. I., Schott, J. M., Stevens,
J. M., Rossor, M. N., and Fox,
N. C. (2002). Mapping the evo-
Alzheimer’s disease: unbiased anal-
ysis of fluid-registered serial MRI.
Proc. Natl. Acad. Sci. U.S.A. 99,
Shaw, L., Vanderstichele, H., Knapik-
Czajka, M., Clark, C., Aisen, P.,
Petersen, R. C., Blennow, K., Soares,
H., Simon, A., Lewczuk, P., Dean,
R., Siemers, E., Potter, W., Lee, V.
M., and Trojanowski, J. Q. (2009).
ing initiative. Cerebrospinal fluid
biomarker signature in Alzheimer’s
subjects. Ann. Neurol. 65, 403–413.
Small, S. A., Perera, G. M., DeLaPaz,
R., Mayeux, R., and Stern, Y. (1999).
Differential regional dysfunction of
the hippocampal formation among
elderly with memory decline and
Alzheimer’s disease. Ann. Neurol.
Squire, L. R. (1992). Memory and
the hippocampus: a synthesis from
findings with rats, monkeys and
humans. Psychol. Rev. 99, 195–231.
Stark, M., Coslett, H. B., and Saffran,
E. M. (1996). Impairment of an
egocentric map of locations: impli-
cations for perception and action.
Cogn. Neuropsychol. 13, 481–524.
Suthana, N. A., Ekstrom, A. D.,
Moshirvaziri, S., Knowlton, B., and
Bookheimer, S. Y. (2009). Human
spatial information. J. Neurosci. 29,
Tierney,M.C., Szalai,J.P.,Snow, W.G.,
Fisher, R. H., Nores, A., Nadon, G.,
Dunn, E., and St. George-Hyslop,
P. H. (1996). Prediction of probable
Alzheimer’s disease in memory-
impaired patients: a prospective
longitudinal study. Neurology 46,
Tolman, E. C. (1948). Cognitive maps
in rats and men. Psychol. Rev. 56,
Visser, P. J., Scheltens, P., Verhey, F. R.,
Schmand, B., Launer, L. J., Jolles,
J., and Jonker, C. (1999). Medial
temporal lobe atrophy and mem-
ory dysfunction as predictors for
dementia in subjects with mild cog-
nitive impairment. J. Neurol. 246,
Vlcek, K. (2011). “Spatial naviga-
tion impairment in healthy aging
and Alzheimer’s disease,” in The
Clinical Spectrum of Alzheimer’s
Therapeutic Strategies, ed. S. De La
Monte (Rijeka, Croatia: Intech),
Weniger, G., Ruhleder, M., Lange,
C., Wolf, S., and Irle, E. (2011).
Egocentric and allocentric memory
as assessed by virtual reality in indi-
viduals with amnestic mild cogni-
tive impairment. Neuropsychologia
Wilkniss, S. M., Jones, M. G., Korol,
D. L., Gold, P. E., and Manning, C.
A. (1997). Age-related differences
in an ecologically based study of
route learning. Psychol. Aging 12,
Conflict of Interest Statement: The
was conducted in the absence of any
commercial or financial relationships
that could be construed as a potential
conflict of interest.
Received: 01 April 2012; paper pend-
ing published: 23 April 2012; accepted:
07 June 2012; published online: 21 June
Citation: Gazova I, Vlcek K, Laczó J,
Nedelska Z, Hyncicova E, Mokrisova I,
Sheardova K and Hort J (2012) Spatial
physiological and pathological aging.
Front. Ag. Neurosci. 4:16. doi: 10.3389/
Laczó, Nedelska, Hyncicova, Mokrisova,
Sheardova and Hort. This is an open-
access article distributed under the terms
of the Creative Commons Attribution
Non Commercial License, which per-
mits non-commercial use, distribution,
and reproduction in other forums, pro-
vided the original authors and source are
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June 2012 | Volume 4 | Article 16 | 6