Prevención de la infección por VRS en el domicilio

AD typically begins insidiously and progresses slowly. The disease involves a wide spectrum of clinical presentations (for reviews of the neuropsychological profile of AD see Salmon & Bondi, 2009; Weintraub, Wicklind, & Salmon, 2012) that generally follow neuronal and synaptic loss occurring initially in the entorhinal cortex and hippocampus and subsequently in associative temporo-parietal regions (Harper et al., 2017; Shi, Liu, Zhou, Yu, & Jiang, 2009). The extent of cognitive impairment and dementia severity parallels the extent of neocortical neuropathological changes (for a review, see Nelson et al., 2012). The sequence in which cognitive functions first show deterioration generally begins with episodic memory, while deficits in visuospatial abilities, executive functioning, and language are also prominent clinical presentations. After the initial appearance of amnesic symptoms, cognitive deterioration may be detained for up to three years (Haxby, et al., 1992). However, as the disease progresses, cognitive impairment becomes broader and the rate of decline gradually accelerates. Patients with moderate disease severity exhibit some level of impairment on almost all cognitive tasks (Caccappolo-Van Vliet et al., 2003). Late in the disease course, there is general loss of cognitive functions, with aphasia, apraxia, and various agnosias becoming prominent problems. In a very general sense, the pattern of functional regression has been considered as the inverse of normal developmental stages (Emery, 2000). The focus here will be on the characteristics of the early stages of AD with mild dementia severity.

Memory. The hallmark clinical symptom of AD is slow, progressive impairment in episodic memory, characterized by deficits in the acquisition and retrieval of recently learned information (Galton, Patterson, Xuereb, & Hodges, 2000; Ivanoiu et al., 2005; for review see Gallagher & Koh, 2011). Recent advances in neuroimaging offer the opportunity to

investigate the progressive disruption of functional and structural networks over the course of AD (Chhatwal et al., 2013; Myers et al., 2014; Petrella et al., 2011). The topographic

evolution of the pathophysiological processes of AD, detected by PET amyloid imaging, initially targets brain regions of high connectivity, designated as “cortical hubs” (Buckner et al., 2009). These brain regions overlap specific brain networks, including the default mode

164 network (Buckner et al., 2005; Lustig et al., 2003) that project heavily to the medial temporal lobe system (for a review, see Sperling et al., 2010), thought to play a key role in both

memory encoding and retrieval processes. Disruption of the intrinsic connectivity of these networks in AD patients has also been observed during resting state (Greicius, Srivastava, Reiss, & Menon, 2004; Supekar et al., 2008; Wang et al., 2006, 2007; Zhou et al., 2008). In addition, numerous functional neuroimaging studies have reported functional abnormalities in these regions during memory tasks (e.g., Celone et al., 2006; Maestu et al., 2003; Sperling et al., 2003), employing either verbal (e.g., Rémy, Mirrashed, Campbell, & Richter, 2005) or visuospatial (e.g., Rombouts et al., 2005) stimuli (for meta-analysis see Schwindt & Black, 2009; Terry, Sabatinelli, Puente, Lazar, & Miller, 2015; for a review see Dickerson & Sperling, 2008).

Subtle deficits of verbal (Backman, Small, & Fratiglioni, 2001; Lim et al., 2014) and nonverbal (Iachini et al., 2009) anterograde episodic memory appear in very mild or preclinical stages of AD. Numerous studies have consistently shown that patients with AD exhibit substantial impairments on episodic memory tests of various cognitive procedures (e.g., free recall, recognition, paired-associate learning) across different modalities (e.g., auditory, visual) and information (e.g., verbal, visuospatial) (for reviews see Didic et al., 2011; Koen & Yonelinas, 2014). Changes in episodic verbal memory, typically assessed with list-learning tasks or free recall tasks of short stories, are evident even before structural changes become apparent in MRI (Jedynak et al., 2015), and seem to be more robust

predictors of progression from mild cognitive impairment to AD than other biomarkers such as cortical thickness (Gomar et al., 2011). Longitudinal studies corroborate that preclinical AD selectively impairs episodic memory recall and recognition, while core short-term and working memory abilities are less affected (Albert, Moss, Tanzi, & Jones, 2001; Backman et al., 2001; for a meta-analysis see Backman, Jones, Berger, Laukka, & Small, 2005),

reflecting the damage occurring initially in the hippocampal formation (Villemagne et al., 2013) and the compromised interconnectivity between medial temporal lobe regions and neocortical areas (Sperling et al., 2010).

The extent of retrograde amnesia in AD may present a temporal gradient, with remote events less affected compared to recent ones during the early stages of the disease (Sadek et al., 2004; Sagar, Cohen, Sullivan, Corkin, & Growdon, 1998), although some studies have failed to find similar life-epochs effects (e.g., Irish et al., 2011). This temporal gradient may reflect that, while the entorhinal cortex and hippocampus are essential for the acquisition and consolidation of new memories, long-term memories are supported by a wider multifocal

165 neocortical network (Squire & Alvarez, 1995). Moreover, as in typical ageing, where the content of autobiographical memories shifts from episodic to semantic (Piolino et al., 2002), an episodic-to-semantic shift may become further pronounced in AD (Meulenbroek et al., 2010), perhaps as a compensation to the compromised episodic memory capacity. Moreover, disturbances in prospective memory (i.e., the ability to remember to perform a planned action at a future point in time [McDaniel & Einstein, 2011]) are common manifestations of AD (Dermody, Hornberger, Piguet, Hodges, & Irish, 2016; Duchek, Balota, & Cortese, 2006) and have been associated with episodic memory dysfunction and the degradation of a distributed network of the brain involved in memory (Dermody et al., 2016; for a review on future- oriented thinking in neurodegenerative syndromes, see Irish & Piolino, 2015).

Language and semantic knowledge. While certain domains of language remain intact until late stages of AD, several expressive and receptive language functions start to decline early in the course of the disease in a significant proportion of AD patients (for reviews see Szatloczki et al., 2015; Taler & Phillips, 2008; Verma & Howard, 2012). While deterioration in the quality, quantity, and meaningfulness of verbal production and comprehension is primarily thought to result from declines in semantic levels of language processing, language impairment may also be influenced by other symptoms, such as concentration and executive deficits. Moreover, episodic memory dilapidation can substantially hamper the quality of verbal communication (Dijkstra, Bourgeois, Allen, & Burgio, 2004), as AD patients tend to regularly repeat themselves and have difficulties in following a conversation string.

Nevertheless, the basic mechanical principles of language, such as syntax and lexical

structure and articulation, appear to remain well preserved in AD patients (Croot et al., 2000). In the earliest stages of AD, subtle language deficits involve word-finding and lexical retrieval difficulties (Blair, Marczinski, Davis-Faroque, & Kertesz, 2007; Mendez, Clark, Shapira, & Cummings, 2003), poorer verbal fluency (Henry, Crawford, & Phillips, 2004; Murphy, Rich, & Troyer, 2006), and diminished comprehension with increased syntactic and grammatic complexity (Tsantali, Economidis, & Tsolaki, 2013). Progressive disintegration of semantic memory becomes evident once the neuropathology of the disease spreads to the temporal, frontal and parietal association neocortex (Adlam, Bozeat, Arnold, Watson, & Hodges, 2006; Rogers & Friedman, 2008; for review see Hodges & Patterson, 1995). Patients with mild dementia often perform poorly on tests reflecting semantic processing (e.g.,

Hodges, Salmon, & Butters, 1992; Joubert et al., 2010; Rogers, Ivanoiu, Patterson, &

Hodges, 2006). These include picture-confrontation naming of objects (e.g., Faust, Balota, & Multhaup, 2004; Balthazar et al., 2008; Lin et al., 2014) and verbal fluency (Raoux et al.,

166 2008; Tierney, Yao, Kiss, & McDowell, 2005; for meta-analyses and reviews, see Henry, Crawford, & Phillips, 2004; Laws, Duncan, & Gale, 2010), as well as semantic categorization (Aronoff et al., 2006) and matching conceptually related pictures (Peraita, Diaz, & Anello- Vento, 2008).

The underlying nature of these lexico-semantic deficits has been debated as to whether they result from deterioration in the structure and content of semantic knowledge or from impaired operations of effortful access and retrieval of semantic information. The fact that AD patients consistently perform poorly across different tasks requiring semantic processing, including semantic categorization (Aronoff et al., 2006) or matching conceptually related pictures (Peraita et al., 2008), has led to the assumption that these deficits emerge from semantic degradation. However, studies using lexical-decision priming paradigms have found intact semantic priming effects for certain types of semantic relationships (i.e., category superordinates [e.g., apple-fruit] and coordinates [e.g., cherry-apple]) in AD patients, despite their poor performance in explicit semantic memory tasks, suggesting that their semantic deficits emerge from deficient explicit retrieval in combination with a partially degraded semantic network (Rogers & Friedman, 2008). In line with this, semantic impairment in AD patients has been associated with cortical atrophy in the anterior temporal lobe and inferior prefrontal cortex (Joubert et al., 2010). AD patients exhibit impaired attribute semantic priming (Rogers & Friedman, 2008), particularly for distinctive attributes (e.g., stripes-zebra) compared to shared attributes (e.g., duck-feathers) (Laisney et al., 2011). These findings, in accordance with distributed models of semantic representations, support a gradual hierarchic semantic deterioration in AD, where loss of distinctive attribute knowledge (Catricalà et al., 2015) causes close concepts to merge (e.g., zebra-horse). As concepts lose their

distinctiveness, thinking may become more vague and communication may become poorer in content.

Visuospatial cognition. Patients at an early stage of AD typically display impaired visuospatial abilities, as demonstrated by several different means involving both small and larger scales of space. Studies involving figural space using paper-and-pencil tasks that require integration of visual information have reported impaired visuospatial perception (e.g., Simard, van Reekum, & Myran, 2003; Quental, Brucki, & Bueno, 2013), visuoperceptual organization (Paxton et al., 2007), and visuoperceptual discrimination (Alegret et al., 2009) abilities, as well as poorer ability of mentally rotating objects (Lineweaver, Salmon, Bondi, & Corey-Bloom, 2005). Impairments in visuoconstructional abilities, such as clock drawing

167 (Leyhe et al., 2009) or copying complex figures (Serra et al., 2010) are also well documented in AD patients.

The deterioration of visuospatial perception abilities during the amnesic preclinical stages of AD seems to be attributable to alterations in the connectivity of fronto-parieto- temporal regions as well as functional alterations in these regions (Jacobs et al., 2015).

Marked widespread neuronal dysfunction, extending the hippocampus, has also been reported in amnesic prodromal AD patients during encoding of object-location binding associations (Hampsted, Stringer, Stilla, Amaraneni, & Sathian, 2011). Furthermore, several studies with AD patients have shown impairment on dorsal stream functions, such as motion perception (Mapstone, Dickerson, & Duffy, 2008; Thiyagesh et al., 2009) and spatial location matching (Bokde et al., 2010).

Visuospatial impairments among AD patients also occur in larger-scale space. Brief episodes of spatial disorientation or getting lost in familiar surroundings are among the earliest manifestations of AD (Monacelli, Cushman, Kavcic, & Duffy, 2003; Pai & Jacobs, 2004; Serino & Riva, 2013), consistent with the neuropathological impact of the disease on the medial temporal lobes and parietal cortex. Apart from spatial disorientation in familiar environments, patients with mild AD also display poor navigation abilities in new

environments and are deficient at learning the locations of landmarks, as demonstrated by route-learning tasks (e.g., Cushman et al., 2008; Rankin, Mucke, Miller, & Gorno-Tempini, 2007; Tu et al., 2015; Tu, Spiers, Hodges, Piguet, & Hornberger, 2017; Yew, Alladi, Shailaja, Hodges, & Hornberger, 2013). Spatial orientation impairments have been attributed to

atrophy of the right posterior hippocampal and parietal areas (Rankin et al., 2007), as well as the retrosplenial cortex (Tu et al., 2015), which is considered to be a neural hub with multiple projections to occipital, temporal, and parietal lobe structures and thus playing a critical role in processing and integrating visuospatial information in order to construct internal

representations of space (Iaria, Chen, Guariglia, Ptito, & Petrides, 2007; Rao, Zhou, Zhuo, Fan, & Chen, 2003; Vann, Aggleton, & Maguire, 2009). AD-associated deficits in spatial orientation and navigation have been observed in tasks requiring both egocentric- and

allocentric-based representations (e.g., Cherrier, Mendez, & Perryman, 2001; Cushman et al., 2008; Moodley et al., 2015; Hort et al., 2007; Tu et al., 2015, 2017; Weniger et al., 2011).

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Chapter 7 Spatial language in early Alzheimer’s disease