Behavioural NeurologyDifferential language network functional connectivity alterations in Alzheimer's disease and the semantic variant of primary progressive aphasia
Introduction
The typical presentation of Alzheimer's disease (AD) is most often characterized by an insidious and progressive decline in episodic memory. Nevertheless, language is also frequently impaired in AD patients (Verma & Howard, 2012). While word-finding difficulties are recognized as the most prominent language deficits (McKhann et al., 2011), verbal fluency (Hodges and Patterson, 1995, Huff et al., 1986, Verma and Howard, 2012), and semantics (Joubert et al., 2010) are frequently impaired in AD as well. These symptoms are also the clinical hallmark of the semantic variant of primary progressive aphasia (svPPA). svPPA is characterized by impaired naming, impaired word comprehension, impaired object knowledge, and surface dyslexia/dysgraphia (Gorno-Tempini et al., 2011). A partial overlap of language symptoms, especially in language production, can therefore be observed in AD and svPPA. However, these impairments are not present in all AD patients and are overall less severe in comparison to svPPA patients (Montembeault et al., 2017, Reilly et al., 2011, Rogers and Friedman, 2008, Sajjadi et al., 2012).
Classic neuroanatomical models of language, mainly based on post-stroke aphasic patients, postulate that language is sustained by two main language centers, namely Broca's area (left pars triangularis/pars opercularis in the inferior frontal gyrus – IFG) and Wernicke's area (left posterior middle temporal gyrus – pMTG) (Geschwind, 1970). Although the precise function and localization of these regions have been the object of a longstanding debate, their role within the language network is widely accepted (Dronkers et al., 2017, Tremblay and Dick, 2016). Further studies, mainly based on observations on svPPA patients, have however revealed the critical role of the left ATL within the language network, mainly in conceptual knowledge (Chedid et al., 2016, Heilman, 1972, Hodges et al., 1992, Snowden et al., 1989, Wilson et al., 2012). Although it was initially omitted from the classic language model, there is now extensive support for its inclusion as a main language center in addition to the left IFG and the left pMTG (Damasio et al., 2004, Ferstl et al., 2008, Hurley et al., 2015, Mesulam et al., 2013, Schwartz et al., 2009, Ueno et al., 2011).
Consistently, the development of language symptoms in AD and svPPA is associated with a dysfunction in one or more of these three key language regions. Neuroimaging studies in AD patients have indeed shown that language impairments are associated with changes in functional activity or hypometabolism in the left IFG (Melrose et al., 2009, Teipel et al., 2006), the left pMTG (Nelissen et al., 2007, Nelissen et al., 2011, Vandenbulcke et al., 2007) and the left ATL (Hirono et al., 2001, Lars et al., 2016, Zahn et al., 2004). In svPPA, studies have more consistently attributed naming and semantic impairments to dysfunction of the left ATL (Acosta-Cabronero et al., 2011, Desgranges et al., 2007, Diehl et al., 2004, Wilson et al., 2012).
However, in addition to dysfunction in specific and isolated brain regions, it is now recognized that functional disconnection within brain networks can underlie the cognitive impairments observed in neurodegenerative disorders such as AD and svPPA (Guo et al., 2013, Seeley et al., 2009). Resting-state functional magnetic resonance imaging (rs-fMRI) is one of the neuroimaging techniques that allows the investigation of functional brain networks. This task-free fMRI method examines the interactions between brain regions through correlated changes in blood-oxygen-level dependent (BOLD) signal. In recent years, the language network has been studied and successfully characterized in healthy controls using this technique (Hurley et al., 2015, Tomasi and Volkow, 2012). In cognitively unimpaired elderly adults, Hurley and colleagues have confirmed that the left IFG, the left pMTG and the left ATL are functionally interconnected and form the rs-fMRI language network (Hurley et al., 2015). These key regions are also connected with the left angular gyrus and the left superior frontal gyrus (see visual representation of the rs-fMRI language network, based on Hurley et al., 2015, presented in Fig. 1). This suggests that rs-fMRI could be a tool of choice to better understand network-level brain alterations underlying language symptoms in clinical populations such as AD and svPPA. To our knowledge, only a very few studies have assessed functional connectivity in the language network in these populations and none has directly compared AD and svPPA patients.
In AD patients, the majority of rs-fMRI studies have focused on the default-mode network (DMN) (Buckner et al., 2005). These studies have shown a disconnection between the regions of the DMN, most frequently the hippocampus, the precuneus and the posterior cingulate cortex (for a recent review, see Badhwar et al., 2017). More recently, studies observed functional connectivity alterations even beyond the DMN in AD patients. This extended interest to other brain networks such as the language network (Mascali et al., 2018, Weiler et al., 2014, Whitwell et al., 2015). The few rs-fMRI studies investigating the language network in AD patients have consistently reported lower resting-state functional connectivity in posterior temporal language regions (such as the left pMTG) (Mascali et al., 2018, Weiler et al., 2014, Whitwell et al., 2015). Anterior frontal language regions (such as the left IFG) have yielded less consistent results, studies showing preserved (Weiler et al., 2014) or altered (Mascali et al., 2018) functional connectivity. Nonetheless, in most of these studies, language was not the main focus. Furthermore, none of them has investigated functional connectivity in the left ATL, even though recent rs-fMRI studies support its inclusion in the language network of healthy individuals (Hurley et al., 2015). Given the role of this region in language impairments in AD patients (Apostolova et al., 2008, Brambati et al., 2006, Brambati et al., 2009, Brambati et al., 2015, Domoto-Reilly et al., 2012, Grossman et al., 2004, Lars et al., 2011), it would be necessary to investigate its functional connectivity.
In svPPA patients, only two studies have investigated the language rs-fMRI network. Both studies demonstrated the functional isolation of the left ATL (Agosta et al., 2014, Guo et al., 2013). More specifically, this key region has been shown to be disconnected from several primary and associative cortical regions, and its reduced functional connectivity correlates with naming deficits in svPPA patients (Guo et al., 2013). Nonetheless, the functional connectivity in other parts of the language network remains unclear in these patients.
In this study, we aim to directly compare the rs-fMRI language network in AD patients, svPPA patients and cognitively unimpaired elderly adults (CTRL). In order to provide a full picture of the language network in these patients and to fill the gaps in the previous literature on this topic, regions of interest will be placed in the left IFG, left pMTG and left ATL. Given that language impairments are present in both populations, we hypothesize that significant alterations in the rs-fMRI language network will be observed in both AD and svPPA patients. In AD patients, although language impairments have been associated with isolated functional/metabolic changes in all key regions of the language network, we aim to determine if functional connectivity is also disrupted in these regions in AD patients. Based on the few previous rs-fMRI studies in this population (Mascali et al., 2018, Weiler et al., 2014, Whitwell et al., 2015), we hypothesize that functional disconnection will be predominant from the left pMTG. In svPPA, based on the few previous rs-fMRI studies (Agosta et al., 2014, Guo et al., 2013), we hypothesize that functional disconnection will be predominant from the left ATL, but we also aim to explore if functional connectivity changes are also observed in other key regions of the language network. The results of this study could support the notion that language impairments in AD and svPPA are sustained by distinct disconnection patterns across the language network. They could also contribute to the understanding of the nature of language impairments in these two patient populations.
Section snippets
Participants
This study included ten patients with a clinical diagnosis of AD, twelve patients diagnosed with svPPA and eleven CTRL. These three groups were matched for age, gender, and education. Demographics of participants are presented in Table 1. The AD and svPPA patients were recruited through the Clinique interdisciplinaire de Mémoire du Centre hospitalier universitaire (CHU) de Québec and referred by a behavioral neurologist with expertise in neurodegenerative diseases and cognition (R.J.L.).
Neuropsychological and language measures
Scores of each group and between-group differences in neuropsychological and language measures are presented in Table 1. Overall, both patient groups presented significant language impairments in comparison to CTRL, and svPPA patients showed more severe language impairments in comparison with AD.
More specifically, in comparison to CTRL, AD patients were significantly impaired in naming and verbal fluency (free and semantic conditions). In comparison to CTRL, svPPA patients were impaired on all
Discussion
In this study, we directly compared the rs-fMRI language network in AD patients, svPPA patients and cognitively unimpaired elderly adults (CTRL). Overall, language impairments and language functional network alterations were observed in both populations. However, some differences were observed in the language profiles between AD and svPPA patients, and functional connectivity changes did not target the same regions in these two groups. In AD patients, the left pMTG was the only key language
Acknowledgments
The present work is supported by the Alzheimer Society of Canada (Grant number: 1420). MM is supported by Alzheimer Society of Canada and Fonds de Recherche du Québec Santé (FRQ-S) doctoral awards. MB is supported by Canadian Institutes of Health Research (CIHR) and FRQ-S doctoral awards. MAW is supported by the Réseau Québécois de Recherche sur le Vieillissement (RQRV). RL is supported by Fondation du CHU de Québec and Société Alzheimer de Québec. SMB is supported by a Chercheur-boursier
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