Research reportLost in spatial translation – A novel tool to objectively assess spatial disorientation in Alzheimer's disease and frontotemporal dementia
Introduction
Spatial and temporal disorientation is a well-documented early symptom of Alzheimer's disease (AD) (Hornberger et al., 2010, Pai and Jacobs, 2004, Pengas et al., 2010a, Pengas et al., 2010b, Yew et al., 2013). For patients diagnosed with one of the frontotemporal dementia (FTD) syndromes, however, orientation is reported to be relatively intact (Bellassen et al., 2012, Pengas et al., 2010a, Pengas et al., 2010b, Yew et al., 2013). This raises the question of whether orientation can be used as a discriminant of AD and FTD, in particular, between AD and the behavioural variant of FTD (bvFTD), where significant memory impairment in a subset of bvFTD patients can lead to diagnostic uncertainty (Hornberger et al., 2010).
Spatial navigation in general has been well studied in dementia patients including mild cognitive impairment (MCI), the prodromal stage of AD (for a review see Serino, Cipresso, Morganti, & Riva, 2014). Investigations of orientation in dementia patients, however, have been limited, given the lack of suitable, and practical, tasks that can be easily utilised in a clinical setting. Orientation can be characterised as being either egocentric or allocentric; cognitive processes which are subserved by different brain regions. Egocentric spatial orientation (i.e., location of objects in relation to the self) has been suggested to be dependent on parietal cortices while allocentric spatial orientation (i.e., location of objects in relation to other objects) is critically dependent on medial temporal lobe structures, including the hippocampus (Burgess, Becker, King, & O'Keefe, 2001). Significant structural and metabolic changes are present in the parietal lobe and retrosplenial region (Brodmann Areas 29 and 30) in AD (Nestor et al., 2003, Pengas et al., 2010a, Tan et al., 2013), but not bvFTD (Irish et al., 2014, Tan et al., 2013). Egocentric spatial orientation may be, therefore, a suitable measure to discriminate between the two conditions. The importance of the retrosplenial region for spatial orientation has been highlighted in a case report of a taxi driver who suffered focal left retrosplenial haemorrhage and immediately presented with selective egocentric spatial disorientation (Ino et al., 2007). Evidence from functional imaging studies further suggests that egocentric navigation is subserved by the parietal cortex and, in particular, the retrosplenial cortex (RSC) for heading direction (for a review see, Boccia, Nemmi, & Guariglia, 2014).
The specialised role of the RSC in orientation during spatial navigation has been consistently demonstrated across functional neuroimaging studies (Baumann and Mattingley, 2010, Epstein et al., 2007, Iaria et al., 2007, Marchette et al., 2014). The RSC is the gateway to key occipital, temporal, and parietal lobe structures responsible for processing visual information, constructing an internal model of the environment (allocentric framework) and updating directional information based on movement from the motor system, respectively (Vann, Aggleton, & Maguire, 2009). Consequently, the RSC acts as a neural hub for the integration and processing of egocentric, allocentric and visual information necessary to orientate oneself within an environment (Epstein and Vass, 2013, Vann et al., 2009). Functional imaging studies have consistently shown activity in the RSC in healthy young participants during tasks involving orientation within a learnt virtual environment, when making judgements of relative direction (Baumann and Mattingley, 2010, Epstein et al., 2007, Marchette et al., 2014), and also during active navigation using landmarks as reference (Iaria et al., 2007). Multi-voxel pattern analysis carried out by Marchette et al. (2014) indicated that the location of environmental features, in addition to directional information, is encoded within the neural activity elicited by the RSC.
While the aforementioned studies have implemented behavioural tasks that excel in evoking RSC involvement, assessment of orientation is predicated on the accurate acquisition and formation of an internal representation of a new experimental environment and landmarks (with the exception of Epstein et al., 2007), a process which is critically dependent on the hippocampus (Boccia et al., 2014, Ekstrom et al., 2003, Hirshhorn et al., 2012, Iaria et al., 2007). In patients with episodic memory deficits (i.e., compromised hippocampal function) both the time required, and demands of the initial learning phase would be significantly increased, reducing efficacy in a clinical setting. To our knowledge, the current most ecologically valid assessment of orientation in memory impaired patients involve topographical map assessments of landmarks within a patient's local city or surrounding locale (Campbell et al., 2014, Pai and Yang, 2013), similar to that implemented by Epstein et al. (2007). These tasks, however, are limited to participants familiar with specific environments (i.e., downtown Sydney), but can be overcome as in the case of the personalised versions used by Pai and Yang (2013), where they targeted unique landmarks near each participant's residence. Therefore, a spatial orientation task that does not require prior training and widely applicable to objectively assess memory impaired patients is necessary.
In the current study, we utilised a virtual supermarket environment that does not require prior learning of a spatial layout to assess spatial orientation in AD and FTD. Participants viewed the environment from a first person perspective and maintained spatial orientation using an egocentric frame of reference. Spatial orientation performance was, therefore, dependent on two variables: i) incidental formation of a working egocentric representation of the environment, and ii) updating egocentric memory in response to movement through the environment (Land, 2014). AD, and FTD patients diagnosed with the behavioural (bvFTD) or semantic (SD) variants were tested – both have shown to have hippocampal but not RSC atrophy. We aimed to assess: i) the clinical applicability of the virtual supermarket task in these patient cohorts, ii) sensitivity of spatial orientation as a diagnostic discriminant between AD and bvFTD, and iii) neural correlates of spatial orientation in AD. We hypothesized that while orientation is dependent on memory processes, the retrosplenial region would be critical for egocentric spatial orientation, such that spatial orientation would be associated with reduced structural integrity of the RSC.
Section snippets
Participants
Fifty eight dementia patients (20 AD; 24 bvFTD; 14 SD) and 23 age- and education-matched healthy controls were recruited from the Sydney frontotemporal dementia research group (FRONTIER) database. All participants were assessed at the FRONTIER clinic located at Neuroscience Research Australia, Sydney. Study approval was provided by the South Eastern Sydney Local Health District Human Research Ethics Committee. All participants provided signed consent for neuropsychological assessment and
Demographics and cognitive testing
Participant cohorts were well matched for demographic variables, and patient groups were matched for disease duration and disease severity (Table 1; all p values > .1). ANOVA of participant groups' performance across standard cognitive tests revealed significant group differences for all components (all p values < .003). In the two groups of interest, bvFTD showed a better cognitive profile than AD on the ACE-R screening of general cognition (all p values < .01), verbal memory (RAVLT: T1-5,
Discussion
The current study demonstrated that spatial orientation can be used to discriminate between AD and bvFTD beyond their memory impairment. The virtual supermarket task was successfully used to assess spatial orientation in amnesic dementia patient populations with hippocampal atrophy. Notably, orientation was impaired in AD, but relatively intact in FTD patient groups, even after accounting for differences in performance on episodic memory tasks. Orientation performance showed the same level of
Acknowledgements
We thank Dr. Waterlander for providing the virtual supermarket environment for the current study. This work was supported by funding to Forefront, a collaborative research group dedicated to the study of frontotemporal dementia and motor neurone disease, from the National Health and Medical research Council (NHMRC) of Australia program grant (#1037746), the Australian Research Council (ARC) Centre of Excellence in Cognition and its Disorders Memory Node (#CE110001021) and an ARC Discovery
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