Behavioural NeurologyExamining prefrontal contributions to past- and future-oriented memory disturbances in daily life in dementia
Introduction
Episodic memory disturbances are a prominent feature of many neurodegenerative disorders, attributable to degeneration of key nodes of a core network in the brain (Dickerson & Eichenbaum, 2010). Anchored on the medial temporal lobes and hippocampus, this core network includes prefrontal, inferior parietal, and lateral temporal brain regions, which support the capacity to remember past experiences and to envisage possible future events (Renoult, Irish, Moscovitch, & Rugg, 2019; Schacter et al., 2012). Over the last two decades, important insights have been gleaned by studying the breakdown of episodic memory processes in clinical populations such as dementia (Irish & van Kesteren, 2018), enabling us to refine current neurocognitive models of episodic memory.
The majority of studies to date have focused on Alzheimer's disease (AD) given canonical impairments in encoding, storage, consolidation and retrieval in this syndrome (Dickerson & Eichenbaum, 2010) which extend to visuospatial (Salimi et al., 2019; Tu et al., 2015) and self-referential forms of memory (Wong et al., 2017). Collectively, these difficulties reflect degeneration of medial temporal, prefrontal and posterior parietal brain structures (Irish, Piguet, Hodges, & Hornberger, 2014). These episodic memory impairments are paralleled by a profound inability to envisage possible future events (Addis, Pan, Vu, Laiser, & Schacter, 2009; Irish, Addis, Hodges, & Piguet, 2012a, 2012b) or to remember to carry out actions at a future point in time, so-called prospective memory (Kamminga, O'Callaghan, Hodges, & Irish, 2014; Lecouvey et al., 2019). While only a handful of studies have investigated the neural substrates of future-oriented expressions of memory in AD, the available evidence suggests that loss of integrity in prefrontal and posterior parietal regions contributes strongly to these impairments (Dermody, Hornberger, Piguet, Hodges, & Irish, 2016).
Compromised episodic memory function is increasingly recognised in non-Alzheimer's dementias including the behavioural-variant of frontotemporal dementia (bvFTD). BvFTD is predominantly characterised by degeneration of medial prefrontal and lateral temporal brain regions, with variable hippocampal involvement (Rascovsky et al., 2011). Recent studies suggest that performance on standard laboratory-based tasks of episodic memory in bvFTD is affected to the same degree as disease-matched cases of Alzheimer's disease (Bertoux et al., 2014), and correlates strongly with hippocampal and prefrontal atrophy (Frisch et al., 2013; Irish, Piguet, et al., 2014). Autobiographical memory dysfunction has further been documented in bvFTD, resulting in a flat retrieval gradient across all time periods (Irish et al., 2011; Piolino et al., 2003) and attributable to medial prefrontal cortical degeneration (Irish, Hodges, & Piguet, 2013; Piolino et al., 2007). Unsurprisingly, future-oriented expressions of memory are markedly compromised, resulting in an inability to envisage future events (Irish et al., 2013), non-personal public events (Irish, Eyre, et al., 2016), or to carry out simple tasks at a future point in time (Kamminga et al., 2014). These future-oriented deficits have been shown to reflect medial temporal dysfunction including atrophy to the right hippocampus and parahippocampal gyrus (Irish et al., 2013), with prefrontal and medial temporal lobe atrophy implicated in prospective memory dysfunction in bvFTD (Dermody et al., 2016).
Turning our attention to the primary progressive aphasias, patients with semantic dementia (SD) typically perform in line with matched controls on visuospatial or non-conceptually loaded memory tasks (Ikeda, Patterson, Graham, Ralph, & Hodges, 2006; Irish, Bunk, et al., 2016), with relative preservation of recent autobiographical memory retrieval, in the context of compromised remote memory (Irish et al., 2011; Irish et al., 2018; McKinnon, Black, Miller, Moscovitch, & Levine, 2006; Piolino et al., 2003). Notably, despite relatively intact episodic memory for the past, striking impairments in envisaging the future have been documented in SD (Duval et al., 2012; Irish, Addis, Hodges, & Piguet, 2012b) spanning episodic and semantic domains (Irish et al., 2012a). Rather than displaying a global impairment in future-oriented thinking, SD patients demonstrate relatively intact performance on time-based prospective memory tasks (Kamminga et al., 2014), suggesting differential profiles of loss and sparing depending on the type of function assessed and the experimental context in which such behaviours occur (Strikwerda-Brown, Grilli, Andrews-Hanna, & Irish, 2019).
Far less is known regarding the status of episodic memory in the other language variants of primary progressive aphasia, such as logopenic progressive aphasia (LPA) and progressive non-fluent aphasia (PNFA) (Gorno-Tempini et al., 2011). Impaired episodic memory has been observed in LPA across verbal and nonverbal episodic delayed recall measures (Piguet, Leyton, Gleeson, Hoon, & Hodges, 2015; Ramanan et al., 2016), reflecting the progressive breakdown of a frontoparietal-hippocampal network (Ramanan, Foxe et al., 2020; Ramanan, Marstaller et al., 2020). Mild autobiographical memory deficits have been reported in PNFA but are abolished by the provision of memory retrieval probes, suggestive of a strategic retrieval deficit (McKinnon et al., 2008). To our knowledge, no study has explored the capacity for future-oriented expressions of memory in PNFA or LPA patients.
Despite significant implications for functional independence, it remains unclear how impairments in past- and future-oriented expressions of memory impact the everyday life of people living with dementia. Assessment of memory disturbances across past- and future-contexts in daily life in dementia is challenging, given well-documented loss of insight that occurs in many of these syndromes (Mendez & Shapira, 2005). Moreover, the neural substrates of such past- and future-oriented forms of thinking in daily life have not, to our knowledge, been systematically explored. The objectives of this study were twofold. First, we aimed to characterise past- and future-oriented thinking impairments as they manifest in daily life using an ecologically valid questionnaire, the Prospective and Retrospective Memory Questionnaire (PRM-Q; Smith, Della Sala, Logie, & Maylor, 2000). This questionnaire has been validated for carers to provide an ecologically valid snapshot of past- and future-oriented disturbances in daily life. Second, we sought to elucidate the underlying neural correlates of these past- and future-thinking disturbances using whole-brain voxel-based morphometry analyses. Given the importance of medial temporal and prefrontal contributions to everyday memory function (Bailey et al., 2013; Umeda, Nagumo, & Kato, 2006), we predicted that retrospective and prospective memory dysfunction would be most profound in AD and bvFTD groups.
Section snippets
Methods and materials
We report how we determined our sample size, all data exclusions, all inclusion/exclusion criteria, whether inclusion/exclusion criteria were established prior to data analysis, all manipulations, and all measures in the study.
Demographics and clinical characterisation
Demographic and clinical characterisation data are presented in Table 1. Groups showed no significant difference in terms of sex (χ2 (5) = 8.15, p = .15), age (F(5, 148) = .90, p = .49, = .03), but differed for years of formal education (F(5, 148) = 2.49, p = .03, = .08), with the Control group spending on average 2.23 years longer in education than bvFTD patients (p = .02). Direct comparison of patient groups revealed equivalent disease duration (years elapsed since symptom onset: F(4,
Discussion
Everyday disturbances in memory are a common complaint in dementia, yet the neural bases for these impairments remain unclear. Here, we explored how past- and future-oriented expressions of memory during everyday activities are affected in dementia syndromes. Overall, we revealed a global impairment of past- and future-oriented memory, as rated by carers, in AD and bvFTD relative to healthy older Control participants, with no impairments evident in the primary progressive aphasias. We confirm
Funding support
This work was supported in part by funding to ForeFront, a large collaborative research group dedicated to the study of frontotemporal dementia and motor neuron disease, from the National Health and Medical Research Council of Australia program grant (APP1037746) and the Australian Research Council Centre of Excellence in Cognition and its Disorders (CE11000102). LL is supported by a China Scholarship Council scholarship. RA is supported by an NHMRC Early Career Fellowship (GNT1120770). OP is
Author contributions
Lulu Liu: Methodology; Formal analysis; Data curation; Visualization; Writing–Original Draft; Writing–Review & Editing.
Daniel Roquet: Methodology; Software; Formal analysis; Visualization; Writing–Review & Editing.
Rebekah M. Ahmed: Data curation; Investigation; Writing–Review & Editing.
John R. Hodges: Resources; Writing–Review & Editing; Supervision.
Olivier Piguet: Investigation; Resources; Writing–Original Draft; Writing–Review & Editing; Supervision.
Muireann Irish: Conceptualization;
Acknowledgements
The authors are grateful to the research participants and patients' carers for their support of our research. The authors wish to acknowledge the Sydney Imaging and Sydney Informatics Hub funded by the University of Sydney for providing support for human neuroimaging acquirements and computing power.
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