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Neurocase: The Neural Basis of Cognition


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Visual spatial cognition in neurodegenerative


disease
a
Katherine L. Possin
a
Department of Neurology, University of California, San Francisco, CA, USA
Published online: 02 Jun 2010.

To cite this article: Katherine L. Possin (2010): Visual spatial cognition in neurodegenerative disease, Neurocase: The
Neural Basis of Cognition, 16:6, 466-487

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NEUROCASE
2010, 16 (6), 466487

Visual spatial cognition in neurodegenerative disease


GNNCS

Katherine L. Possin
Visual Spatial Cognition in Neurodegenerative

Department of Neurology, University of California, San Francisco, CA, USA

Visual spatial impairment is often an early symptom of neurodegenerative disease; however, this multi-faceted
domain of cognition is not well-assessed by most typical dementia evaluations. Neurodegenerative diseases cause
circumscribed atrophy in distinct neural networks, and accordingly, they impact visual spatial cognition in
different and characteristic ways. Anatomically-focused visual spatial assessment can assist the clinician
in making an early and accurate diagnosis. This article will review the literature on visual spatial cognition in
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neurodegenerative disease clinical syndromes, and where research is available, by neuropathologic diagnoses.
Visual spatial cognition will be organized primarily according to the following schemes: bottom-up/top-down
processing, dorsal/ventral stream processing, and egocentric/allocentric frames of reference.

Keywords: Vision; Dementia; Neuropsychology; Visuospatial; Parkinson disease; Alzheimer disease; Frontotemporal
Lobar Degeneration; Progressive Supranuclear Palsy; Dementia with Lewy bodies.

INTRODUCTION forgetting where they placed their keys or parked


their car. These subtle declines seen in the healthy
When we look at and interact with the visual world elderly are even more pronounced and have a
in all its detail, the process usually feels effortless, greater impact on function in most types of
but in reality highly complex cognitive processes neurodegenerative disease (Amick, Grace, & Ott,
are occurring, enabling us to see, touch objects, 2007; Cormack, Tovee, & Ballard, 2000; Dawson,
navigate, and remember where we have been. Anderson, Uc, Dastrup, & Rizzo, 2009).
Depending on our needs, we must quickly and In this review, I propose a multi-faceted model
accurately direct our attention to what is relevant of visual spatial cognition that can help elucidate
while suppressing what is irrelevant, create brief or the specific patterns of visual spatial dysfunction
lasting visual representations in our minds, associated with Alzheimers disease, Parkinsons
manipulate mental representations to guide our disease, Lewy Body Dementias, Corticobasal
behavior, and find our way through familiar or Syndrome, Progressive Supranuclear Palsy, and
new environments. Thinking about these many Frontotemporal Lobar Degeneration. These
components of visual spatial cognition is not as neurodegenerative disease syndromes impact the
intuitive as thinking about verbal cognition, but brain in characteristic topographic patterns of
spatial cognition is at least as important for neuropathology, particularly during early stages
successful everyday functioning. Elderly persons (Seeley, Crawford, Zhou, Miller, & Greicius, 2009).
with declines in spatial functioning frequently Disease-related impairments in visual spatial cogni-
report difficulties, such as feeling unsafe when tion are manifestations of these anatomic patterns,
driving, having trouble navigating new routes, and and so performance on tests of spatial cognition

This work was supported by 2008-A-020-FEL from the Larry L. Hillblom Foundation. I thank Bruce L. Miller and Joel H. Kramer
for their helpful comments on this manuscript.
Address correspondence to Katherine L. Possin, Ph.D., 350 Parnassus Ste. 905, San Francisco, CA 94143-1207, USA.
(E-mail: kpossin@memory.ucsf.edu).

2010 Psychology Press, an imprint of the Taylor & Francis Group, an Informa business
http://www.psypress.com/neurocase DOI: 10.1080/13554791003730600
VISUAL SPATIAL COGNITION IN NEURODEGENERATIVE 467

can have implications for differential diagnosis and


for monitoring disease progression. The purpose of
this article is to discuss how visual spatial cognition
is impacted by neurodegenerative diseases, and
how these impairments relate to the underlying
pathology.

FACETS OF VISUAL SPATIAL COGNITION

Visual spatial cognition is composed of a multi-fac-


eted set of functions mediated by a predominantly
right-hemisphere network of widely-distributed
brain regions including the parietal lobes, lateral
prefrontal cortex, medial temporal lobes, inferior
temporal cortex, occipital cortex, basal ganglia,
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Figure 1. As visual information travels from primary visual cor-


and white matter tracts. This domain of cognition tex (V1) through secondary and tertiary processing areas (V2
includes skills as diverse as orienting attention and V5), increasingly more complex aspects of visual experience are
navigation learning. In this review visual spatial processed and cells are tuned to larger receptive fields. Color
and form information is processed by a ventral pathway via V2,
cognition is organized primarily according to 3
V4, and inferior temporal cortex. Location and motion
schemes: bottom-up/top-down cognition, dorsal/ information is processed by a dorsal pathway via dorsal V2 and
ventral stream processing, and egocentric/allocen- V3, V5, and posterior parietal cortex.
tric frames of reference.
Visual information is processed in both a
bottom-up and top-down fashion. Bottom-up vis- called MT, is specialized for local motion detection
ual processing in the geniculostriate system follows and receives some direct visual inputs that bypass
a set anatomical and functional pathway from V1 (Zeki, 2008). The dorsal pathway continues to
early sensory processing areas to progressively posterior parietal cortex where complex aspects of
more specialized modules (Barton, 1998). Visual space perception, such as perceiving details of a
information enters the brain through the retina, scene as an integrated percept, are accomplished.
passing through the axons of ganglion cells that Lesions in the earliest visual processing areas, from
form the optic nerve and optic tract. Cells in the the optic nerve to primary visual cortex, result in
geniculostriate system send information through total blindness in all or part of the visual field
the lateral geniculate body of the thalamus and (Stoerig & Cowey, 1997). In contrast, lesions in the
then to the primary visual cortex. The primary visual association areas, where subsequent
visual cortex (V1) sends axons through secondary processing occurs, distort the attributes of visual
and tertiary processing areas (e.g., V2V5) where experience processed by those areas.
cells respond to increasingly complex aspects of Top-down visual processing refers to executive
visual experience and have larger receptive fields aspects, which are primarily mediated by lateral
(see Figure 1). Color and form information pro- prefrontal cortex, parietal cortex, and frontal-stri-
cessing follows a ventral pathway through V2 and atal circuits (Kastner & Ungerleider, 2000; Miller
V4. V2 is tuned to simple attributes of visual & Cohen, 2001). These control system functions
experience such as orientation, spatial frequency, include selecting visual information for detailed
and color, whereas V4 is also tuned to object processing, organizing complex visual information,
features of intermediate complexity such as mediating voluntary shifts of attention, inhibiting
geometric shapes. This pathway continues to infe- irrelevant information, planning how to use visual
rior temporal cortex where progressively more information to achieve behavioral goals, unifying
complex aspects of visual object processing are percepts of ambiguous visual stimuli, and manipu-
accomplished, such as face perception. Bottom-up lating or updating visual information represented
processing of motion and location information in the posterior cortex by bottom-up systems.
follows a dorsal pathway through V2 and V3. Attentional enhancement appears to follow the
Dorsal V3 appears to be specialized for global reverse order of bottom-up systems; for example,
motion detection (Braddick et al., 2001). V5, also earlier and larger responses to attended stimuli are
468 POSSIN

seen in V4 than in V1 (Buffalo, Fries, Landman, rately dorsal and ventral stream processing
Liang, & Desimone, 2009). because it is divided into subtests that emphasize
Top-down systems depend on the integrity of either object or space perception (Warrington &
bottom-up systems. For example, if a patients James, 1991).
ability to perceive or mentally represent where The segregation of where and what informa-
objects are located in space is impaired due to tion is not as clear in the prefrontal cortex, where
bottom-up system compromise, the patient will not there is evidence that the dorsal and ventral areas
be able to manipulate that information in spatial may be segregated by the type of processing
working memory or utilize that information to required as well as the type of information to be
plan a sequence of movements. Performance on processed (Courtney, 2004; Wager & Smith, 2003).
top-down tests should be interpreted relative to Select deficits in top-down aspects of spatial (ver-
performance on tests of more fundamental visual sus object-based or verbal) processing can be seen
processing, such as tests of simple figure copy, in some patients with Parkinsons disease, Cortico-
visual search, judgment of line orientation, and basal Syndrome, and Progressive Supranuclear
face perception (Strauss, Sherman, & Spreen, 2006). Palsy, however, indicating some dissociation for
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Newer test batteries such as the Delis-Kaplan space-based information in frontal-subcortical


Executive Function System include test conditions systems and the need to include executive function
designed to parse out fundamental component tests that utilize space-based information in
skills and isolate executive processes (Delis, dementia evaluations.
Kaplan, & Kramer, 2001). For example, perform- A third critical distinction in visual spatial cog-
ance on a test of complex visuomotor sequencing nition is that of egocentric and allocentric reference
can be evaluated relative to performance on tests of frames. In the egocentric reference frame, object
motor speed, visual scanning, and simple sequencing. locations are processed in reference to the self, and
A second distinction in visual cognition is dorsal this self-based map is updated as we move through
and ventral stream processing. Visual processing the environment. This reference frame is particu-
pathways in the posterior cortex are segregated larly important (1) when we need to update spatial
such that the dorsal regions process space-based information on a moment-to-moment basis as we
where information, and the ventral regions pro- move through the environment and (2) when we
cess object-based what information (see Figure 1) have navigated along the same path so many times
(Ungerleider & Mishkin, 1982). The dorsal path- that our movement along that path becomes
way projects rostrally via the superior longitudinal routine (Ball, Smith, Ellison, & Schenk, 2009; Postle
fasciculus from dorsal occipital cortex to posterior & DEsposito, 2003; Whishaw, 1985). In the
parietal cortex. The posterior parietal cortex in allocentric reference frame, object locations are
each hemisphere is organized primarily for contral- processed in reference to each other or fixed
ateral spatial function, although there is a predom- landmarks, independent of ones position in the
inant role for the right hemisphere in dorsal stream environment. This reference frame is important for
spatial functions in general. The dorsal stream developing cognitive maps (OKeefe & Nadel,
system has close ties with the motor system and 1978). The egocentric frame of reference relies crit-
codes the locations of objects and their movement ically on the dorsal caudate nucleus, the posterior
in terms of how one would acquire or act upon parietal cortex, the precuneus, and the lateral
them. For this reason, the dorsal stream has also frontal cortex (Iaria, Petrides, Dagher, Pike, &
been termed the how stream (Goodale & Milner, Bohbot, 2003; McDonald & White, 1994; Packard
1992). The ventral pathway projects rostrally via & McGaugh, 1992; Postle & DEsposito, 2003;
the inferior longitudinal fasciculus from ventral Spiers & Maguire, 2007; Weniger, Ruhleder, Wolf,
occipital cortex into inferior temporal cortex. This Lange, & Irle, 2009) whereas the allocentric frame
system codes non-spatial features of objects relev- of reference relies on the medial temporal lobe,
ant to their identity, for example color and form. including the hippocampus, and interactions with
Inferior temporal cortex is organized for both con- occipito-temporal (ventral stream) structures
tralateral and ipsilateral function, because inferior (Bohbot, Iaria, & Petrides, 2004; Bohbot, Lerch,
temporal areas receive heavy input from striate Thorndycraft, Iaria, & Zijdenbos, 2007; Byrne,
cortex via the corpus callosum representing the Becker, & Burgess, 2007; Doeller, King, & Burgess,
ipsilateral visual field. The Visual Object and Space 2008; Gramann, Muller, Schonebeck, & Debus,
Perception battery can be used to evaluate sepa- 2006; Iaria, Chen, Guariglia, Ptito, & Petrides,
VISUAL SPATIAL COGNITION IN NEURODEGENERATIVE 469

2007; Maguire et al., 1998). While parietal cortex is


understood to play a critical role in the egocentric
network, it has in some studies been implicated in
the allocentric network (Burgess, 2008; Iaria et al.,
2003), and is likely essential for integrating these
frames of reference.
The vast majority of research on egocentric and
allocentric navigation learning has been conducted
with rodents, and many of these studies have used
adaptations of the Morris Water Maze task (Morris,
1984). In the typical version of this paradigm, a
rodent is placed in a pool of water with a hidden
escape platform. By varying the presence and posi-
tion of extra-maze (distal) cues or intra-maze
Figure 2. A screen shot from an allocentric virtual navigation
(proximal) cues relative to where the rodent is task we are using in our laboratory that is based on the Morris
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placed in the pool, researchers can evaluate the Water Maze. Subjects are virtually placed in a new starting posi-
integrity of different navigation strategies. For tion on each trial and navigate through the circular field to find
example, in one classic version of this task, a rat is a hidden treasure. The subjects must develop a cognitive map
placed in a pool that is surrounded by distal land- of the treasures position relative to the distal cues to find the
treasure because the route changes on each trial.
marks. After it learns the position of the platform,
it is then placed back in the pool at a different
starting point. If the rat executes the same motor
More work is needed to validate and standardize
program (i.e., it swims in the same direction from
allocentric and egocentric tests for clinical
the starting point disregarding the distal land-
purposes.
marks), it is using an egocentric navigation strat-
In this review, the constellations of visual spatial
egy. If the rat changes its motor program to find
cognitive impairments in Alzheimers disease,
the platform based on the constellation of distal
Parkinsons disease, Lewy Body Dementias, Corti-
cues, it is using an allocentric strategy. Research
cobasal Syndrome, Progressive Supranuclear
studies using the Morris Water Maze have demon-
Palsy, and Frontotemporal Lobar Degeneration
strated a critical role for the hippocampus in allo-
will be reviewed with a focus on the facets of visual
centric navigation, and a critical role for the dorsal
spatial cognition, outlined above (see Table 1). It
striatum in egocentric navigation (McDonald &
should be emphasized that in many respects, this
White, 1994; Miranda, Blanco, Begega, Rubio, &
research is in early stages. The impairments will be
Arias, 2006; Pearce, Roberts, & Good, 1998).
related to the topographic patterns of disease-
At present, there are no clinically available tests
related neuropathology. Careful evaluation of spatial
to measure allocentric and egocentric processing.
cognitive functions using anatomically-specific
New virtual reality techniques show promise for
methods can provide information about which
translating insights from studies of allocentric and
neural networks are impacted by the disease, and
egocentric navigation in rodents to the study of
therefore, can assist the clinician in making an
navigation in humans (Cushman, Stein, & Duffy,
accurate early diagnosis and monitoring disease
2008; Weniger et al., 2009). These techniques com-
progression and response to treatment.
bine the rigor and control of laboratory measures
with the ecological validity of real life situations.
For example, our laboratory evaluates allocentric ALZHEIMERS DISEASE
navigation using a virtual reality version of the
Morris Water Maze (Figure 2). Subjects are placed Cortical atrophy in Alzheimers disease (AD) is
in a new starting position on each trial in a circular most pronounced in the medial temporal and
field, and search for a hidden treasure. The only posterior temporoparietal regions (Ishii et al.,
stable referents relative to the treasure are the dis- 2005; Rabinovici et al., 2007). The primary visual
tal landmarks that surround the circular field. cortex tends to be more spared than the visual
Thus, the subject must develop a cognitive map of association areas. Neuropathologically, the earliest
the virtual environment to find the treasure and changes in the typical case occur in the hippocampus
cannot rely on a route-based (egocentric) strategy. and entorhinal cortex and then progress to the
470 POSSIN

TABLE 1
Typical constellation of visual spatial impairments in the early stages of neurodegenerative diseases

Bottom-up/Top-down Dorsal/Ventral Allocentric/Egocentric

Alzheimers disease Bottom-up most patients, Both are often affected Allocentric
although some patients show
top-down
Posterior cortical Bottom-up, all patients Dorsal more than ventral, although Patients cannot use either frame
atrophy both are affected of reference well due to severe
with disease progression bottom-up impairments
Parkinsons disease Top-down Dorsal Egocentric
Lewy body Both, nearly all patients Both, nearly all patients Unknown, likely both in most
dementias patients
Corticobasal syndrome Variable, top-down likely more When visual spatial processing Unknown, likely egocentric
common but in some is affected, dorsal impairments are
patients bottom-up can be usually more severe
prominent, as discussed in
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text
Progressive Top-down attentional Patients have difficulty orienting Unknown, likely egocentric
supranuclear palsy impairment is common spatial attention, but cortical dor-
sal/ventral streams are
usually intact
Behavioral variant Top-down, most patients, Not impaired Unknown, may vary with
frontotemporal although in early stages pathologic subtypes
dementia no visual spatial impairment
may be evident
Semantic dementia and Not impaired Neither impaired early, although SD Not impaired
Progressive may affect ventral stream process-
nonfluent aphasia ing with disease progression

parietal, temporal, and frontal lobes (Braak & Morrison, & Laudate, 2007). Tests of visual cognition
Braak, 1998; Gomez-Isla et al., 1996). Early-onset that require the integration of visual information
cases tend to show less prominent hippocampal processed by separate regions in visual association
involvement, greater atrophy in parietal and cortex can be particularly sensitive to the effects of
occipital cortex, and in many cases more severe AD (e.g., tests of complex figure copy, mental
impairment on visual spatial testing that can rotation, and visual organization; Festa et al.,
present before memory impairment (Frisoni et al., 2005; Freeman et al., 2000; Lineweaver, Salmon,
2007; Fujimori et al., 1998). Bondi, & Corey-Bloom, 2005; Paxton et al.,
AD can impact most aspects of visual processing, 2007), perhaps due to the effects of the disease on
consistent with the impact of the disease on both multiple visual areas that are compounded by
dorsal and ventral stream areas. Patients are these integration tasks. Visual acuity, however, is
impaired in dorsal stream functions such as angle relatively spared (Cronin-Golomb et al., 1991;
discrimination and motion perception (Mapstone, Rizzo et al., 2000), except in patients who present
Dickerson, & Duffy, 2008; Prvulovic et al., 2002; with a Posterior Cortical Atrophy syndrome, dis-
Rizzo, Anderson, Dawson, & Nawrot, 2000; Tippett cussed below.
& Black, 2008), and ventral stream functions such A tendency to get lost is a common and often
as the perceptual discrimination and recognition of early symptom of AD (Monacelli, Cushman,
faces, colors, and objects (Cronin-Golomb, Kavcic, & Duffy, 2003; Pai & Jacobs, 2004), con-
Sugiura, Corkin, & Growdon, 1993; Kurylo et al., sistent with the critical role of the medial temporal
1994; Rizzo et al., 2000). Contrast sensitivity defi- lobes and parietal cortex in navigation learning
cits are also prominent in AD (Gilmore & Levy, and spatial memory (Astur, Taylor, Mamelak,
1991; Hutton, Morris, Elias, & Poston, 1993), and Philpott, & Sutherland, 2002; Burgess, 2008;
enhancing the strength of stimuli has been shown Morris, Garrud, Rawlins, & OKeefe, 1982).
to ameliorate performance on tests of letter identi- Navigation learning has been studied extensively in
fication, word reading, picture naming, and face dis- transgenic mouse models of AD; for example,
crimination (Cronin-Golomb, Gilmore, Neargarder, transgenic hAPP mice with hippocampal damage
VISUAL SPATIAL COGNITION IN NEURODEGENERATIVE 471

are impaired in the use of allocentric cues on a


Morris Water Maze task (Deipolyi et al., 2008). By EEEE HHHHHHHH
translating findings from the rodent literature, EE EE HHHHHHHH
researchers have been able to design tests to evalu- EE EE HH
ate navigation learning in Alzheimers disease in an
anatomically-focused manner. DeIpolyi, Rankin, EEEEEEEE HHHHHHHH
Mucke, Miller, and Gorno-Tempini (2007) tested EEEEEEEE HHHHHHHH
patients with mild AD on a real-world test of navi-
gation learning. The patients were more likely to
EE EE HH
get lost than controls and were deficient at learning EE EE HHHHHHHH
the locations of landmarks, and these impairments EE EE HHHHHHHH
were associated with smaller right posterior
hippocampal and parietal volumes. New virtual Figure 3. Navon figures. Patients with impaired global process-
ing will identify the smaller letters but will fail to identify the
reality techniques are showing promise in transla- global letters (i.e., in this example, they would report seeing only
tional research for refining our understanding of an E in the first figure and an H in the second figure).
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navigation impairments in AD, and tests that


emphasize allocentric navigation may be particularly
sensitive (Bohbot et al., 2007; Burgess, Trinkler,
King, Kennedy, & Cipolotti, 2006; Cushman et al., a complex picture, they would focus on individual
2008; Ishii et al., 2005). elements and were poor at interpreting the overall
scene. In addition, when shown Navon figures,
which are compound figures in which a larger
POSTERIOR CORTICAL ATROPHY
global letter is composed of a different, repeated,
smaller letter (Navon, 1977), the patients were
Posterior Cortical Atrophy (PCA) is a clinical
impaired in identifying the global letter even when
syndrome associated with prominent bottom-up
cued to do so (see Figure 3 for an example of
visual spatial impairments and relative preserva-
Navon figures). Ventral stream aspects of spatial
tion of memory, insight, and judgment (Benson,
cognition, such as recognizing objects, faces, and
Davis, & Snyder, 1988). PCA is associated with
colors, tended to be less impacted than dorsal
atrophy in the occipital, parietal, and posterior
stream aspects (McMonagle et al., 2006; Nestor
temporal lobes (Whitwell et al., 2007a). Pathologi-
et al., 2003).
cally, PCA is usually a form of Alzheimers disease
with greater neurofibrillary tangle burden in the
visual cortex and lower burden in the hippocampus PARKINSONS DISEASE
(Alladi et al., 2007; Tang-Wai et al., 2004). In com-
parison to typical AD cases, PCA patients show The primary neuropathological features of
selective hypometabolism of the occipito-parietal Parkinsons disease (PD) are the formation of
regions, right worse than left (Nestor, Caine, alpha-synuclein inclusion body pathology (Lewy
Fryer, Clarke, & Hodges, 2003). bodies and Lewy neurites) that are distributed
McMonagle, Deering, Berliner, and Kertesz throughout the nervous system (Braak & Del
(2006) characterized 19 patients with PCA. The Tredici, 2008), and the degeneration of the
most common clinical features were primarily dopamine producing cells of the substantia nigra
dorsal stream (occipito-parietal) abnormalities and pars compacta, which project to the striatum (i.e.,
included features of Balints syndrome including the caudate nucleus and putamen; Agid, 1991).
simultanagnosia and optic ataxia, and alexia and Dopamine depletion in the caudate nucleus and its
agraphia out of proportion to other language impact on the frontal-striatal circuits is thought to
abnormalities that do not rely on visual processing. be the primary substrate of cognitive sequelae
In addition, when presented with hierarchically (DeLong & Wichmann, 2007; Marie et al., 1999;
constructed stimuli, the patients demonstrated Owen, 2004; Sawamoto et al., 2008). Circuits crit-
impairments at processing the global features, ical for top-down control and dorsal stream pro-
which is consistent with right hemisphere dysfunc- cessing are particularly affected. Dopamine
tion (Delis, Robertson, & Efron, 1986; Robertson, depletion in the caudate nucleus is uneven with the
Lamb, & Knight, 1988). For example, when shown greatest loss in the anterodorsal extent of the head
472 POSSIN

(Joyce, 1993; Kaufman & Madras, 1991; Kish, objects as well as locations; for example, inhibition
Shannak, & Hornykiewicz, 1988), a subregion is greater when objects surround the cues and
which receives massive projections from the targets, presumably because inhibition is directed
dorsolateral prefrontal cortex and posterior parietal to both the location of the cue and the object
cortex (Baizer, Desimone, & Ungerleider, 1993; associated with the cued location (Leek, Reppa, &
Yeterian & Pandya, 1991, 1993). Tipper, 2003). PD patients have shown reduced
Patients with PD without dementia typically inhibition of return associated with a cued loca-
show numerous strengths on neurocognitive test- tion, but when the stimuli display was altered so
ing. For example, these patients generally perform that objects surrounded the cues and targets; the
within normal limits or show very mild impairment patients showed the same magnitude of inhibition
on tests tapping language, episodic memory, of return as controls (Possin et al., 2009). These
abstract reasoning, problem solving, concept results suggest that the patients were impaired at
formation, and bottom-up visual cognition. PD inhibiting their attention in a space-based frame of
has subtle and circumscribed effects on aspects of reference but were able to overcome their impair-
working memory and attention, however, that can ment when they could direct their attention to
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impact everyday functioning (Salmon & Filoteo, objects.


2007; Uc et al., 2007). Several studies have exam- Attention deficits in PD appear to be mediated
ined the nature of these impairments. In general, by impaired inhibitory processes (Filoteo, Rilling,
working memory for spatial information is more & Strayer, 2002; Gurvich, Georgiou-Karistianis,
impaired than working memory for object-based Fitzgerald, Millist, & White, 2007). Although
or verbal information, particularly during early nondemented PD patients often perform similarly
disease stages (Owen, Iddon, Hodges, Summers, & to neurologically healthy individuals on tests that
Robbins, 1997; Postle, Jonides, Smith, Corkin, & require the facilitatory aspects of orienting
Growdon, 1997). Whereas verbal working memory (Bennett, Waterman, Scarpa, & Castiello, 1995;
is often intact for simple span tasks but impaired Goldman, Baty, Buckles, Sahrmann, & Morris,
for complex span tasks (e.g., involving the mental 1998), they frequently are impaired when condi-
manipulation of memoranda), spatial working tions promote a conflict between task-relevant and
memory is impaired for both simple and complex irrelevant information, such as on tests of selective
span tasks (Siegert, Weatherall, Taylor, & Aber- attention (Filoteo, Maddox, Ing, & Song, 2007),
nethy, 2008). The spatial working memory deficit negative priming (Mari-Beffa, Hayes, Machado, &
appears to emerge after very brief maintenance Hindle, 2005), set shifting (Downes et al., 1989),
intervals (e.g., 1 s) and not worsen with increasing and inhibition of return. Inhibitory attention and
intervals, which suggests that the selective spatial working memory involve overlapping processes,
impairment involves an early stage of working and space-based and object-based aspects of these
memory processing, such as encoding or attention processes are functionally and neurally separable
(Possin, Filoteo, Song, & Salmon, 2008). (Chou & Yeh, 2008; Simmonds, Pekar, & Mostofsky,
The nature of attentional impairment in PD has 2008; Zhou & Chen, 2008). It may be at this
been examined, and there is some evidence that intersection of working memory and inhibitory
space-based aspects of attention are the most attention, for space-based information in particular,
impacted, similar to the pattern of working that PD patients can show their earliest cognitive
memory deficits. For example, PD patients have impairments.
shown a selective impairment in space-based inhi- It is not known whether PD patients show more
bition of return (Possin, Filoteo, Song, & Salmon, impairment in egocentric aspects of space-based
2009), an attentional phenomenon thought to be processing than allocentric aspects, but there is
critical for efficient visual search (Posner & Cohen, reason to suspect based on the impact of PD
1984). Typically, when a persons attention is cued pathology on caudate nucleus function that the
to a location in the periphery, a target presented in disease may have a greater impact on egocentric
that location enjoys an immediate processing processing. Packard and McGaugh (1996) showed
advantage as compared to a target presented in that when rats were given lidocaine injections to
another location. However, if more than 300 ms inactivate the hippocampus, allocentric place
elapses following the cue, attention is biased away learning was impaired, i.e., the rats were not able
from the cued location in favor of novel locations. to use the location of distal cues to choose the arm
This inhibition of return can be directed at of a maze where food is located. In contrast, rats
VISUAL SPATIAL COGNITION IN NEURODEGENERATIVE 473

given injections to inactivate the dorsolateral convergence of these disorders and the value of
caudate nucleus were impaired in using an egocentric treating them as overlapping entities when investi-
response strategy, i.e., the rats could not learn to gating and treating the underlying neurobiology
follow a path such as turning left irrespective of (Lippa et al., 2007).
distal cues. A similar double dissociation has been The neuropsychological phenotype of both
shown using fMRI while human subjects per- PDD and DLB involves pronounced visual spatial,
formed a virtual reality navigation task (Iaria et attention, and executive impairments (Metzler-
al., 2003). Subjects who used distal cues to navigate Baddeley, 2007; Troster, 2008). According to most
showed increased activation in the right hippocam- studies that have compared these disorders, when
pus, whereas subjects who used a response strategy matched on overall severity of dementia, they
showed increased activation in the caudate differ minimally in their patterns of cognitive
nucleus. Although research is needed to directly impairment and both disorders are associated with
compare egocentric to allocentric spatial cognition parkinsonism, attentional fluctuations, and visual
in PD, these patients have shown evidence of hallucinations (Aarsland et al., 2003; Ballard et al.,
disrupted egocentric cognition including con- 2002; Janvin et al., 2006; Noe et al., 2004). Over-
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stricted representations of the distances between lapping pathologic substrates of DLB and PDD
their body and external space (Lee, Harris, Atkin- include a-synuclein pathology, neuronal loss, and
son, & Fowler, 2001; Skidmore et al., 2009) and degeneration of the basal forebrain. Alpha-synu-
shifts in egocentric midline estimation such that clein pathology in the central nervous system
patients with predominantly left-sided motor progresses in a characteristic and ascending
symptoms have shown a rightward shift, and pattern from the olfactory tract and the brainstem,
patients with predominantly right-sided motor to the nigrostriatal system, to cortex (Braak & Del
symptoms have shown a leftward shift (Davidsdottir, Tredici, 2008). Cortical atrophy is less severe and
Wagenaar, Young, & Cronin-Golomb, 2008). widespread than in AD (Whitwell et al., 2007b).
Cholinergic depletion is more severe in Lewy body
dementias than in AD, and both DLB and PDD
LEWY BODY DEMENTIAS patients have shown improvements in attention
after taking cholinesterase inhibitors (Emre et al.,
Dementia is a frequent complication of Parkinsons 2004; Giladi et al., 2003; Rowan et al., 2007). One
disease. Prevalence estimates are about 30% in difference in the neuropathology between DLB
community based samples of individuals with and PDD is that a co-association with Alzheimers
Parkinsons disease (Aarsland, Zaccai, & Brayne, pathology is more common in DLB, which may
2005), and recent longitudinal studies indicate that contribute to the more rapid progression to
approximately 80% of Parkinsons patients dementia relative to the onset of motor symptoms
develop dementia before death (Galvin, Pollack, & (Edison et al., 2008; Gomperts et al., 2008).
Morris, 2006; Hely, Reid, Adena, Halliday, & Numerous studies have focused on identifying
Morris, 2008). Onset of dementia in PD is more neuropsychological variables that allow discrimi-
rapid in patients with a non-tremor dominant nation between Lewy body dementias and AD (for
phenotype and in patients who show posterior cor- a more comprehensive review on this topic, see
tical impairments on neuropsychological testing, Troster, 2008). These studies are important
including visual spatial construction impairment because compared to patients with AD, patients
(Burn et al., 2006; Williams-Gray, Foltynie, with Lewy body dementia may show greater
Brayne, Robbins, & Barker, 2007). response to cholinesterase inhibitors (Perry et al.,
In contrast to patients with Parkinsons disease 1994; Tiraboschi et al., 2002) and abnormal sensi-
with dementia (PDD), patients with Dementia with tivity to neuroleptic drugs (Aarsland et al., 2005).
Lewy Bodies (DLB) show cognitive impairment The overall pattern emerging from these studies is
prior to or within one year of extrapyramidal that Lewy body dementia patients show more
motor symptoms (Emre et al., 2007; McKeith et severe and pervasive visual spatial, attentional, and
al., 2005). Other than the chronology of symptom executive impairments than AD, whereas AD
progression, these disorders are much more similar patients show more severe memory impairment.
than they are different. The DLB/PDD Working Visual spatial deficits are a particularly important
Group proposed the umbrella term Lewy body component of differential diagnosis from AD
dementias to reflect the clinical and pathological (Aarsland et al., 2003; Collerton, Burn, McKeith,
474 POSSIN

& OBrien, 2003; Johnson, Morris, & Galvin, Consistent with these findings, both DLB and AD
2005). Although patients with AD are frequently patients show hypoperfusion and hypometabolism
impaired on tests of visual spatial construction, in the parietal and temporal lobes, but only DLB
patients with Lewy body dementia are usually patients show hypoperfusion and hypometabolism
more impaired on these tests early in the disease. in the occipital lobes including the primary visual
For example, patients with DLB frequently fail to cortex (Lobotesis et al., 2001; Minoshima et al.,
copy accurately the interlocking pentagons on the 2001; Sato et al., 2007; Shimizu et al., 2008), which
MMSE even when global cognitive impairment is is the most critical cortical region for early aspects
mild (Hanyu et al., 2006; Tiraboschi et al., 2006). of bottom-up visual processing. Abnormalities in
Tiraboschi et al. (2006) demonstrated that the morphology and synuclein expression in the retina
presence of visual spatial impairment early in the may also impact visual perception in DLB (Maur-
course of dementia substantially improved the age, Ruchoux, de Vos, Surguchov, & Destee,
sensitivity of predicting pathology-proven DLB 2003).
versus pure AD. An absence of visual spatial Visual hallucinations are common in Lewy body
impairment had a negative predictive value of 90%, dementias, and appear to share an overlapping
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which was higher than visual hallucinations or neural basis with visual perceptual disturbance.
extrapyramidal signs. Identification of visual spatial Both visual hallucinations and visual perceptual
impairment is important not only for designating impairments have been related to Lewy body
individuals whose clinical syndrome is impacted pathology in neocortex (Tiraboschi et al., 2006;
more by Lewy body formation than AD pathology, Williams, Warren, & Lees, 2008), hypoperfusion
but also for predicting which patients with DLB and hypometabolism in the dorsal and ventral
will have a more malignant disease course (Hamilton visual pathways (Matsui et al., 2007; Mori, Ikeda,
et al., 2008). Fukuhara, Nestor, & Tanabe, 2006; Perneczky
Performance on construction tasks in Lewy et al., 2008), and cholinergic dysfunction (Bohnen
body dementias is affected by impairments in et al., 2006; McKeith, Wesnes, Perry, & Ferrara,
visual perception and pre-attentive visual process- 2004). Visual hallucinations have been associated
ing. These early aspects of bottom-up visual cogni- with Lewy body counts in the amygdala, parahip-
tion are typically more impaired in Lewy Body pocampal, and inferior temporal cortices (Harding,
dementias than AD, and likely play an important Broe, & Halliday, 2002), which suggests a ventral
role in their more severe construction deficits. DLB stream basis for this clinical feature. In contrast, an
patients are more impaired than AD patients on inverse relationship between persistent visual
tests of visual search, with more severe relative hallucinations and tangle pathology has been
impairment on parallel pop-out search in contrast reported (Ballard et al., 2004). Typically, halluci-
to top-down serial search (Cormack, Gray, nations are complex visions of animals or people,
Ballard, & Tovee, 2004; Noe et al., 2004). Calderon occur daily for minutes at a time, and are experi-
et al. (2001) compared patients with DLB to enced as unpleasant by the patient (Mosimann
patients with AD on the Visual Object and Space et al., 2006). Visual hallucinations, like visual spa-
Perception Battery (Warrington & James, 1991), a tial impairment, are useful for determining whether
set of tasks that emphasize bottom-up aspects of a patients clinical syndrome is impacted by Lewy
visual cognition and place minimal demands on body pathology (Tiraboschi et al., 2006; Williams
motor functions. DLB patients showed more et al., 2008).
severe impairments than AD patients on tests
tapping both ventral stream (Fragmented Letters
and Object Decision) and dorsal stream (Cube CORTICOBASAL SYNDROME
Analysis) aspects of visual perception. Similarly,
Mosimann et al. (2004) found that DLB and PDD Corticobasal syndrome (CBS) characteristically
patients showed more severe impairments than AD presents with asymmetric rigidity and apraxia with
patients on tests tapping both ventral stream (tests additional cortical (e.g., alien limb, cortical sensory
of object and form perception) and dorsal stream loss, myoclonus) and basal ganglia (e.g., bradyki-
function (tests of dot position and motion percep- nesia, dystonia) dysfunction (Boeve, 2007b).
tion). These comparisons of bottom-up visual Diagnostic criteria emphasize a motor disorder,
spatial processing suggest more severe posterior but there is increasing recognition that cognitive
cortical dysfunction in Lewy body dementia. impairment and even dementia can present before
VISUAL SPATIAL COGNITION IN NEURODEGENERATIVE 475

motor dysfunction (Litvan et al., 2003; Litvan spatial function is a manifestation of the heteroge-
et al., 1999). A recent CBS criteria consensus neous patterns of cortical dysfunction associated
conference will soon propose new criteria that will with the syndrome, including the side of the brain
need to be tested prospectively (personal communi- most affected by the disease and the degree of
cation). Cognitive impairment profiles are quite posterior involvement. Rare cases have been
variable; for example, patients presenting with reported where visual spatial dysfunction appeared
greater left hemisphere pathology show marked as the first symptom. Tang-Wai et al. (2003)
language impairment, whereas patients presenting described two such patients, one whose initial
with greater right hemisphere pathology show symptoms included difficulty following printed
marked visual spatial dysfunction (Boeve, 2007b). material from line to line, drawing simple configu-
This syndrome has been historically linked to other rations, and reading and writing despite a preserved
akinetic-rigid diseases like Parkinsons disease ability to listen to books on tape and dictate her
because of the presence of extrapyramidal features, thoughts. A second patients early symptoms
but there is increasing recognition that this included difficulty in identifying coins, writing and
syndrome has more in common with a subset of manipulating objects, telling time, and differentiat-
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frontotemporal lobar degeneration disorders ing right from left. These patients showed a greater
(which are discussed below), both because of the burden of tau pathology in the visual association
frequency of tau pathology and because of the (Case 1) and posterior parietal cortex (Case 2) than
overlap of cognitive and behavioral features in other patients with CBD. Although visual spatial
some patients (Josephs, 2008; Mathuranath, dysfunction is rarely such a prominent feature of
Xuereb, Bak, & Hodges, 2000). early CBS as it was in these cases, there is some
Corticobasal degeneration (CBD) is a neu- evidence that when visual spatial impairments are
ropathologic diagnosis characterized by atrophy, apparent, they may tend to involve more dorsal
gliosis, and tau-immunoreactive pathology in the stream than ventral stream functions. For example,
neocortex, basal ganglia, and substantia nigra Bak, Caine, Hearn, and Hodges (2006) found that
(Ludolph et al., 2009). Historically, CBD was CBS patients were more likely to be impaired on
considered to be a distinct clinico-pathologic entity space-based than object-based subtests of the
presenting with CBS (Rebeiz, Kolodny, & Rich- Visual Object and Space Perception Battery. This
ardson, 1968), but it is now understood that CBD pattern of greater dorsal stream impairment is con-
frequently presents in other clinical syndromes, sistent with the parietal and striatal dysfunction
most often bvFTD and PNFA (Boeve, 2007a). Fur- and relative preservation of the temporal cortex in
ther complicating the diagnostic picture, only about CBS (Seeley et al., 2009).
half of patients presenting with the clinical diagno- CBS patients can show difficulty on tasks that
sis of CBS have CBD pathologically, whereas other require them to integrate spatial information with
common neuropathologic diagnoses include Alzhe- motor function. These patients can show impaired
imers disease, progressive supranuclear palsy, and representation of how to use objects despite rela-
Picks disease (Alladi et al., 2007). Although several tively intact object recognition (Silveri & Ciccarelli,
neuropathologic diagnoses can cause CBS, there is 2007). In pre-dementia stages of the syndrome, ges-
a characteristic distribution of pathology associated ture representation is typically intact and patients
with this syndrome, predominantly involving the can comprehend gestures, but gesture production
frontal and parietal cortex and the basal ganglia is frequently impaired; i.e., they know how to
and tending to start asymmetrically (Boeve et al., gesture but are unable to do it (Jacobs et al., 1999;
1999; Boxer et al., 2006; Gibb, Luthert, & Marsden, Zadikoff & Lang, 2005). Similarly, Negash et al.
1989). The temporal cortex, including the medial (2007) demonstrated that CBS patients were able
temporal lobe, is relatively spared. to implicitly learn the structure of a spatial
Visual spatial dysfunction can be a prominent sequence that was visually presented to them, but
component of the clinical presentation of CBS they were unable to accurately execute that
(Bak, Crawford, Hearn, Mathuranath, & Hodges, sequence. This pattern of impairment is consistent
2005; Tang-Wai et al., 2003), although it should be with the disproportionate effects of the disease on
noted that many patients present without clear the dorsal stream regions in cortex, including the
visual spatial impairment (Borroni et al., 2008; superior aspect of the parietal lobules (Boxer et al.,
Murray et al., 2007). This heterogeneity in visual 2006).
476 POSSIN

PROGRESSIVE SUPRANUCLEAR PALSY per se. To properly evaluate spatial cognition in


PSP, it is critical to select tests that allow the
Progressive supranuclear palsy (PSP), or Steele- examiner to disentangle spatial cognition from
Richardson-Olszewski syndrome, is characterized ocular motility. For example, to assess visual
clinically by supranuclear gaze palsy, postural construction, a PSP patient could be asked to draw
instability and falls, and akinetic-rigid features a figure rather than copy a figure.
(Boeve, 2007b; Steele, Richardson, & Olszewski, Using a paradigm that does not rely on oculo-
1964). The most striking pathologic feature of PSP motor function, Posner and Rafal demonstrated
is atrophy in the midbrain tegmentum, and atro- that PSP patients show slowed covert orienting of
phy is also seen in the pons, striatum, and frontal attention and reduced inhibition of return that are
cortex (Boxer et al., 2006). Hypometabolism has most pronounced in the vertical plane (Posner,
been reported in the brainstem, medial thalamus, Choate, & Vaughan, 1985; Rafal, Posner, Friedman,
caudate nucleus, and medial frontal cortex (Eckert Inhoff, & Bernstein, 1988). In the orienting of
et al., 2008). PSP shares clinical features with CBD attention task, a preparatory cue appeared in one
including atypical parkinsonism, and these disor- of 4 squares that were positioned above, below,
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ders are genetically related and both associated and on each side of a central fixation cross. After a
with deposits of 4R tau. PSP is also pathologically brief delay, a target appeared in one of the 4
distinct, however, and is associated with greater squares. Subjects were instructed to press a key as
midbrain atrophy and less severe cortical atrophy quickly as possible when the target appeared. Eye
than CBD (Boxer et al., 2006; Groschel, Kastrup, gaze was maintained on the fixation cross in the
Litvan, & Schulz, 2006). PSP has historically been center of the display. Response times were faster
considered a classic example of subcortical demen- for all subjects when the target appeared in the
tia because the cognitive and behavioral features same square as the cue, but the response time
are attributed to the effects of the disease on advantage was reduced for PSP patients in the
subcortical regions and corresponding frontal lobe vertical plane. The vertical covert orienting and
deafferentation whereas posterior cortex functions inhibition of return impairments could not be
are relatively spared (Magherini & Litvan, 2005). attributed to ocular dysfunction because in these
As compared to patients with CBS, patients with tasks the display was small; eye movements were
PSP in general show less severe impairments on monitored; and the visual orienting deficits were
tests of spatial cognition including visual construc- present even at cue-target intervals as short as 50
tion tests, likely reflecting the relative preservation ms, which is much shorter than the latency for
of posterior cortex in PSP (Bak et al., 2005, 2006; saccades in normal individuals. Robbins et al.
Garbutt et al., 2008). PSP patients can show (1994) examined attentional set-shifting in PSP
marked impairments, however, on tests that rely using a task that required subjects to shift their
on vertical eye movements, vertical shifts of covert attention between two superimposed figures.
attention, and on certain aspects of top-down Because the figures were superimposed, eye move-
spatial attention and working memory. ments were not required. Patients with PSP or PD
PSP is associated with dramatic eye movement were impaired on the task, but not patients with
abnormalities including impaired saccade velocity, early AD, which suggests that the impairment was
saccade gain, and anti-saccades (Garbutt et al., due to subcortical dysfunction. PSP patients can
2008). Vertical saccades tend to be twice as slow as also show impairments on tests of spatial working
horizontal saccades (Bhidayasiri et al., 2001). memory, visual search, and the efficient use of
Successful performance on many tests of spatial spatial strategies (Robbins et al., 1994; Soliveri
cognition relies on vertical saccades, for example, et al., 2000).
tests of figure copy, the Block Design subtest from
the Weschler Adult Intelligence Scale (Wechsler,
1997), the Benton Judgment of Line Orientation FRONTOTEMPORAL LOBAR
Test (Benton, Varney, & Hamsher, 1978), and the DEGENERATION
Number-Location subtest from the Visual Object
Space Perception Battery. PSP patients can show Frontotemporal lobar degeneration (FTLD) is a
deficits on these classic spatial tests (Bak et al., progressive neurodegenerative disease that prima-
2006; Garbutt et al., 2008; Soliveri et al., 2000), but rily affects the frontal and anterior temporal lobes.
these deficits may not reflect spatial impairment, Critical visual spatial processing regions in cortex
VISUAL SPATIAL COGNITION IN NEURODEGENERATIVE 477

(the parietal, inferior temporal, and occipital prefrontal cortex (Krueger et al., 2009; Rahman
cortex) are relatively spared. This pattern of et al., 1999). Patients with bvFTD often make
sparing allows many FTLD patients to perform numerous repetition errors on tests of design flu-
strikingly well on tests of visual spatial skills when ency, even in early stage disease, and the propen-
other aspects of cognition and behavior are sity to make these errors has been associated with
severely impaired. As compared to patients with orbitofrontal atrophy (Chester et al., 2009). As the
AD matched on measures of global cognitive disease progresses and there is more substantial
impairment, FTLD patients perform better on dorsolateral prefrontal cortex and striatal dysfunc-
tests of visual spatial construction (Diehl & Kurz, tion, executive dysfunction and its impacts on spa-
2002; Hutchinson & Mathias, 2008; Rascovsky, tial cognition become even more prominent.
Salmon, Hansen, & Galasko, 2008; Rascovsky Although bvFTD patients generally outperform
et al., 2002). The differential diagnosis of FTLD AD patients on figure copy tests (Diehl & Kurz,
from AD can in some cases be difficult, and assess- 2002; Elfgren et al., 1994; Mendez et al., 1996;
ment of this relative preservation of visual spatial Rascovsky, Salmon, Hansen, & Galasko, 2008;
function in FTLD patients can improve diagnostic Rascovsky et al., 2002), they have been equally
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accuracy (Harciarek & Jodzio, 2005; Thompson, impaired in some studies when the figure to be cop-
Stopford, & Neary, 2008; Rascosky et al., 2002). ied is quite complex (Frisoni et al., 1995; Kramer
FTLD is a heterogeneous disorder, however, and et al., 2003; Lindau, Almkvist, Johansson, &
so understanding spatial cognition in these patients Wahlund, 1998; Pachana, Boone, Miller, Cum-
requires consideration of the different neurobehav- mings, & Berman, 1996; Perry & Hodges, 2000).
ioral syndromes and neuropathologic subtypes. On these tests, such as the Rey-Osterrieth Complex
Figure, performance is known to be influenced by
frontally-mediated executive skills such as organi-
Behavioral variant frontotemporal dementia
zation, strategic processing, and working memory
(Choi et al., 2004; Freeman et al., 2000; Hernandez
FTLD presents in 3 neurobehavioral syndromes
et al., 2003; Varma et al., 1999) in addition to bot-
depending on the distribution of pathology
tom up visual-spatial perception and integration
(Gorno-Tempini et al., 2004; Hodges, 2001; Neary
skills. Whereas AD patients are more likely to make
et al., 1998; Snowden, Neary, & Mann, 2007), and
spatial errors on these tests, suggesting an underly-
these syndromes are associated with subtle differ-
ing impairment in visual spatial processing, bvFTD
ences in spatial cognitive functioning. The behavioral
patients are more likely to make organizational or
variant of frontotemporal dementia (bvFTD) is the
perseverative errors with preserved spatial configu-
most common of these 3 syndromes, and is associ-
ration, suggesting an underlying impairment in
ated with bilateral frontal, anterior insular, and
executive functioning (Thompson et al., 2005).
anterior cingulate involvement with pronounced
orbitofrontal atrophy early in the disease (Perry et
al., 2006). Clinically, these patients show an early Semantic dementia and progressive
decline in social and personal conduct, emotional nonfluent aphasia
blunting, and loss of insight. Consistent with the
relative preservation of the posterior cortex, mild The two aphasic variants of FTLD syndromes are
bvFTD patients usually perform normally on tests semantic dementia (SD) and progressive nonfluent
that assess bottom-up visual spatial perception, aphasia (PNFA). SD is associated with pro-
such as the subtests of the Visual Object and nounced anterior temporal lobe atrophy and often
Spatial Perception Battery (Perry & Hodges, 2000; begins unilaterally. When the disease begins in the
Rahman, Sahakian, Hodges, Rogers, & Robbins, left hemisphere, the patients show a progressive
1999; Thompson, Stopford, Snowden, & Neary, loss of knowledge about words and objects (Amici,
2005). Deficits on tests of spatial cognition can be Gorno-Tempini, Ogar, Dronkers, & Miller, 2006).
seen in bvFTD when the test relies on certain When the disease begins in the right hemisphere,
aspects of top down control. Visual discrimination patients may show relatively subtle language
reversal learning and inhibition of spatial attention, deficits, loss of semantic information about visual
in particular, can be impaired even early in the information such as faces, and more pronounced
disease when the site of pathology involves behavioral dysfunction such as loss of empathy,
predominantly ventral and medial aspects of compulsive behavior, or behavioral disinhibition
478 POSSIN

(Rankin et al., 2006; Rosen et al., 2006). Progressive Cummings, Read, & Mishkin, 2000; Miller & Hou,
nonfluent aphasia (PNFA) is associated with pro- 2004; Seeley et al., 2008).
nounced left inferior frontal and insular atrophy.
PNFA is characterized by hesitant, effortful, and
apraxic speech, agrammatism, and early preserva- Neuropathologic subtypes of frontotemporal
tion of word meaning (Amici et al., 2006). PNFA lobar degeneration
patients are more behaviorally appropriate than
the other variants (Rosen et al., 2006). Patients The majority of FTLD spectrum disorders are
with SD and PNFA rarely show any impairment defined according to 2 neuropathologic subtypes:
on spatial cognitive tasks that do not rely on one with tau positive inclusions (most commonly
language skills; for example, they can normally CBD, PSP, or Picks) and one with inclusions that
copy complex figures (Gorno-Tempini et al., stain positively for TDP-43. BvFTD patients are
2004). When SD patients do show difficulty with about evenly split according to these neuropatho-
the naming of visually-presented objects, this is logic subtypes, whereas the majority of PNFA
attributed to their semantic knowledge impairment patients are tau positive and the majority of SD
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rather than a perceptual problem, per se (Woollams, patients are tau negative (Josephs et al., 2006;
Cooper-Pye, Hodges, & Patterson, 2008). Kertesz, 2009; Llado et al., 2008). A third less
Some patients with SD or PNFA have developed common subtype that presents as bvFTD was
a novel interest in producing art that seems to be recently discovered with fused in sarcoma (FUS)
triggered by the illness, as reported in several case positive TDP-43-negative inclusions (Neumann
studies (Miller et al., 1998; Miller, Ponton, Benson, et al., 2009). Studies that compare antemortem
Cummings, & Mena, 1996; Seeley et al., 2008). cognitive profiles of neuropathologic subtypes are
This art can take on a compulsive quality: patients critically important because scientists are develop-
may repeat the same painting several times, photo- ing promising new treatments that target specific
graph the same subject from multiple angles, or molecules. Grossman et al. ( 2007) compared tau
take hours to complete single lines in each painting positive and tau negative patients, and showed that
(Miller et al., 1998; Miller & Hou, 2004). In SD, the tau positive patients were more impaired, on
distortions of space, color, faces, and other aspects average, on a figure copy test. Clinical syndromes
of composition are prominent (Finney & Heilman, were mixed in the tau positive group; the most
2007; Rankin et al., 2007), and significant symbol- common presentations were CBS (8), social or
ism or abstraction is typically lacking, consistent executive disorder (7), and PNFA (5). As discussed
with the left anterior temporal lobe degeneration above, CBS can be associated with profound
that is the hallmark of this disease (Miller & Hou, spatial impairment, and so this group difference in
2004). spatial function may have been driven by the large
The neural mechanism underlying these bursts number of CBS patients in the tau-positive group.
of artwork and alterations in visual creativity is Within a clinical syndrome, patients may differ
controversial. In these patients, brain disease is in their clinical presentation depending on the
initially focal, anterior, and left-hemisphere pre- underlying neuropathology. Tau-positive and
dominant. The posterior cortex, and notably the FUS-positive bvFTD has been associated with
right posterior cortex, is relatively preserved. These more severe striatal atrophy (Kim et al., 2007;
patients may develop visual spatial creative skills Neumann et al., 2009; Seelaar et al., 2009) and
because they practice using these skills to compen- tau-positive bvFTD has been associated with
sate for their impaired linguistic functions. Some dorsolateral bifrontal atrophy (Whitwell et al.,
have argued that perceived increases in visual 2005) whereas TDP-positive FTLD patients
creativity may be due to emerging dysfunction in often show hippocampal sclerosis (Josephs &
the visual cortical system (i.e., visual distortions Dickson, 2007; Josephs, Whitwell, Jack, Parisi, &
that may be artistically appealing were not done Dickson, 2006). Based on these topographic
for effect; Finney & Heilman, 2007). Others have patterns of pathology, one might hypothesize
argued that the emergence of artwork in these that tau- or FUS-positive bvFTD patients might
patients may represent released inhibition of right show more impairment in spatial functions medi-
posterior cortex, such that the disease process par- ated by frontal-striatal systems such as spatial
adoxically facilitates a more vivid and connected working memory and attention, whereas TDP-43
perception of the visual world (Miller, Boone, positive patients might show more difficulty on
VISUAL SPATIAL COGNITION IN NEURODEGENERATIVE 479

hippocampally-mediated functions such as spatial dysfunction and can provide some diagnostic
orientation and allocentric aspects of navigation. information (e.g., a patient with LBD is likely to
As large enough multi-center samples become show more severe impairment than a patient with
available, it will be critical for future studies to AD), patients can fail the test for several reasons.
report the antemortem profiles of patients For example, a patient with bvFTD may fail a test
according to both clinical syndrome and pathologic of figure copy due to impairments in top-down
subtype. control processes; a patient with PSP may fail the
test due to oculomotor dysfunction; and a patient
with posterior cortical atrophy may fail the test
CONCLUSION
due to simultagnosia. Visual spatial evaluations
should be designed to specifically evaluate the
Visual spatial cognition involves the perception,
facets of visual spatial cognition that may be
selection, organization, and utilization of location
disrupted by the syndromes on the differential. In
and object-based information, and provides a
most cases the battery should include some evalua-
structure for how we interact with our physical
tion of top-down spatial processing, and both
environments. This multi-faceted domain of
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dorsal and ventral aspects of bottom-up systems.


cognition depends on a widely-distributed and
At present, pharmacologic treatments for neuro-
predominantly right hemisphere network of brain
degenerative diseases are limited, but scientists are
regions. As mental representations of the visual
on the verge of developing promising new treatments
world move anteriorly from primary visual cortex
including molecule-specific therapies. As these
through bottom-up systems, progressively more
treatments become available, it will become criti-
complex and integrated aspects are processed.
cally important to identify accurately patients early
Representations in posterior cortex are selected
in the disease course. Neurocognitive evaluations
top-down for further processing by frontal
should aspire to diagnose not only clinical
systems. Dorsal regions of cortex are specialized
syndromes but also neuropathologic subtypes,
for processing the locations of objects and how to
which will ultimately be the target of treatments.
act on them, whereas ventral regions are special-
Methods developed in a cognitive neuroscience
ized for processing features of objects relevant to
framework that can tease apart the integrity of
their identity. This dorsal/ventral distinction is
neural systems can be adapted for clinical use.
particularly relevant to bottom-up systems, but
Refinement of visual spatial evaluation methods is
top-down aspects of spatial processing can be
a promising avenue for improving early diagnostic
selectively affected in patients with frontal-subcor-
accuracy and treatment monitoring.
tical system compromise (e.g., PD). Separable
frames of reference for processing self-based (ego-
Original manuscript received 13 July 2009
centric) and world-based (allocentric) information Revised manuscript accepted 13 January 2010
have been well-elucidated by cognitive neuro- First published online 2 June 2010
science; the egocentric network is anchored by the
dorsal striatum and the allocentric by the medial
temporal lobe. Standardized tests to evaluate this REFERENCES
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