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People share information about where different objects are located in the natural environment almost on a daily basis. Apprehending verbally encoded locative information is therefore a crucial skill for numerous daily activities and in various social contexts. As previously discussed (see Section 2.2), mental representations of space can be communicated under different reference frames and perspectives, including self-centred, other-person-centred, object-centred, and environment-centred frames. The present study employed a novel task (VCSRF; see Section 3.2.4) to examine verbal comprehension of locative relations between two objects under these distinct spatial reference frames in patients at an early stage of AD.

187 Overall, mild AD patients were significantly less accurate in judging descriptions of spatial relations between two objects placed in the natural environment, compared to matched controls. This deficit was demonstrated across all reference frames considered. Notably, patients performed well above chance levels within a self-centred (about 82% correct) and an object-centred (75% correct) perspective, while their performance was just above chance level from a third-person-centred perspective (62%) and below chance level in the

environment-centred frame (40%), whilst controls performed above chance level across all reference frames (see again Figure 29). The theoretical implications of the present findings extend to how spatial relations are mentally represented from different perspectives based on verbal inputs. The fact that patients’ performance varied as a function of the reference frame employed indicates that at least partially distinct operations are involved in mentally

representing space under different frames. By extent, these distinct cognitive operations must be supported by at least partially dissociable neural networks that are differentially affected by the AD pathological processes.

Adopting a third-person-perspective to frame spatial relations from verbal cues elicited the largest differences between mild AD patients and controls. Neuroimaging studies with healthy young adults have shown that posterior parietal regions, and specifically the

precuneus, is involved in visuospatial imagery and third-person perspective transformations during mental viewpoint rotations (David et al., 2006; Lambrey, Doeller, Berthoz, & Burgess, 2012; for a review see Cavanna & Trimble, 2006). Moreover, increased activity in the

precuneus has also been reported in processing sentences with a concrete spatial meaning (Wallentin et al., 2005) and in verbally-cued recalling of spatial relations (Wallentin,

Roepstorff, Glove, & Burgess, 2006; Wallentin, Weed, Ostergaard, Mouridsen, & Roepstorff, 2008) in healthy young adults. Meanwhile, subtle changes in functional precuneus activity during visual encoding have been reported in preclinical stages of AD (Rami et al., 2012) while patients at an early stage of AD also exhibit significant reduction in precuneal volume (Ryu et al., 2010; Stricker et al., 2012). Although spatial third-person perspective taking has not been directly examined in AD patients, several studies have reported diminished social third-person perspective taking and theory of mind abilities (Ramanan et al., 2017),

especially in the later disease stages (for a meta-analysis see Bora, Walterfang, & Velakoulis, 2015). Neuroimaging evidence has shown that mild AD patients recruit prefrontal regions but not visual associative areas when taking a third-person perspective for social judgements, suggesting that they rely more on reasoning processes than on visual imagery strategies (Ruby et al., 2009).

188 The finding of severely impaired performance under an environment-centred spatial reference frame is consistent with the large literature reporting poor allocentric spatial processing in mild AD. Importantly, our findings extend this literature by showing that this system is also diminished when accessed through language. It is well documented that AD patients experience significant difficulties in forming both egocentric (self-centred) and allocentric (environment-centred) representations of space. This has been evidenced in numerous AD studies employing virtual reality tasks for spatial orientation, wayfinding and route learning and memory and has been repeatedly attributed to hippocampal damage (e.g., Morganti, Stefanini, & Riva, 2013; Serino, Morganti, Di Stefano, & Riva, 2015; Tu et al., 2015, 2017; Yew et al., 2013; for a review see Serino et al., 2014). Patients with mild AD also show altered functional responses in brain regions associated with encoding of visual scenes, including medial temporal lobe and fusiform regions, although no such activation abnormalities are observed in occipital areas, reflecting a progressive activation deficit from primary through higher order areas of the ventral visual pathway (Golby et al., 2005). Along with hippocampal regions, the retrosplenial cortex with its strong connections to temporal, parietal, occipital, and frontal regions seems to play a key role in integrating and transforming visuospatial information within different reference frames (Vann, Aggleton, & Maguire, 2009) and has been associated with poor orientation in AD patients (Tu et al., 2017).

Patients were significantly less accurate in processing descriptions of spatial relations from an object-centred reference frame compared to a group of matched controls. However, this group discrepancy was substantially milder compared to the group differences observed in the other non-self-centred reference frames, i.e., the third-person- and environment-centred frames. This finding may be explained by the quantitative and qualitative differences in the mental integration and transformation operations required in these distinct frames. The reference object also defined the reference frame in the object-centred condition, thus putting less processing demands on the relevant cognitive resources. Moreover, the reference object used in this frame was a car model, which holds rich situation knowledge. Therefore, object- knowledge effects might have influenced the processing of spatial relations (cf. Coventry & Garrod, 2004, 2005) by triggering implicit simulations of self-based mental rotations (Kessler & Rutherford, 2010; Kessler & Thomson, 2010; Michelon & Zacks, 2006).

To conclude, using the novel VCSRF task we demonstrated significant impairments in verbal processing of spatial relational information under different spatial reference references in mild AD. The VCSRF, especially in the third-person-centred perspective, produced

189 excellent specificity and sensitivity values establishing its diagnostic validity in accurately discriminating early AD patients from age-, education-, and gender-matched controls.

7.5 Conclusions

This series of studies constituted a first attempt to systematically investigate different aspects of spatial language processing, including production, memory, and comprehension, in

patients at an early stage of AD. The findings extend the large existing literature reporting significant impairments in various spatial abilities in early AD by demonstrating for the first time that spatial processing is also compromised when assessed through language. Crucially, these further support the hypothesis of a supramodal cognitive system that enables flexible representations of space within the verbal and perceptual domain.

Apart from the aforementioned theoretical contributions, the present findings have direct clinical implications as they offer fresh insights into AD patients’ mental functioning during the early stages of the disease, and enrich our knowledge of their cognitive profile with regards to generating, apprehending, and remembering spatial information from verbal descriptions. As we established the novel spatial language tests’ discriminative validity, an interesting avenue for future work will be to assess these functions in individuals at risk of developing AD, as well as across different clinical populations with cognitive impairments. The use of spatial language measures in conjunction with other cognitive markers can enhance the sensitivity and specificity of AD diagnosis.

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