Prospective Memory Impairments in Alzheimer’s Disease and Behavioral Variant Frontotemporal Dementia: Clinical and Neural Correlates

INTRODUCTION

Episodic memory dysfunction represents one of the most prominent and characteristic features of Alzheimer’s disease (AD) [1], widely interpreted as reflecting the degeneration of the medial temporal lobes, most notably the hippocampus [2]. Episodic memory impairments in AD are cross-modal extending across standard neuropsychological tests of visual and verbal recall [3] and include the retrieval of personally relevant autobiographical memories from the past [4, 5]. While the hippocampus has been ascribed a central role in the origin of memory deficits in AD, the importance of regions beyond the medial temporal lobes in supporting successful episodic memory functioning is recognized. Notably, atrophy in parietal regions, such as the posterior cingulate cortex, and prefrontal cortices also contributes to episodic memory dysfunction in AD [6, 7].

The behavioral-variant of frontotemporal dementia (bvFTD) is a form of younger-onset dementia characterized clinically by progressive deterioration in interpersonal conduct and personality, executive dysfunction, and emotion dysregulation [8]. These features are attributable to the degeneration of orbitomesial frontal and anterior temporal lobe regions in the brain, particularly the anterior cingulate cortex and the frontoinsular cortex [9, 10]. Mounting evidence, however, reveals marked episodic memory impairments in bvFTD, at a level comparable to that observed in disease-matched cases of AD [6, 11]. These memory deficits are attributable to the degeneration of predominantly medial and lateral prefrontal, and medial temporal lobe structures including the hippocampus [6]. Thus while episodic memory appears comparably affected in bvFTD and AD, the underlying neural substrates of these deficits diverge contingent on dementia subtype [6, 7].

Prospective memory (PM) refers to a sub-branch of episodic memory whereby an individual must remember to perform a planned action or intention at some point in the future [12] and can be fractionated into Time- versus Event-based components depending on the type of cue which prompts recall of the planned activity. Time-based PM involves remembering to do something at a particular time or following a specific period of time whereas Event-based PM involves remembering to do something in response to an external cue. The ability to remember to do something at a later point in time allows us to think and plan beyond the present moment and is essential for successful everyday adaptive functioning. Accordingly, PMdysfunction considerably limits the capacity to function independently and is associated with a decline in independent activities of daily living, difficulties with financial management, and poor medication adherence [13, 14].

Successful PM performance draws upon multiple cognitive processes, including retrospective memory, planning, inhibition, task switching, and sustained attention or monitoring [15, 16]. This complexity is reflected at the neural level. Prefrontal regions, including the rostral prefrontal cortex (BA10), consistently activate during PM performance in healthy individuals potentially reflecting intention maintenance [17, 18]. Lesions to prefrontal regions have been shown to significantly compromise PM function [19, 20], corroborating the neuroimaging findings. Regions beyond the frontal lobes are also implicated in successful PM function. For example, parietal activation may support allocation of attention toward external stimuli and the PM intention, as well as maintenance and retrieval of the intention itself [18]. Moreover, medial temporal lobe regions, including the hippocampus, are implicated in the retrieval of an action or recognition of a cue during PM tasks [21, 22]. Finally human lesion studies [19] and functional neuroimaging studies [21, 23] point to occipital involvement, with the suggestion that representations of the PM cue may be stored in occipital sites [23]. As such, the evidence to date reveals a distributed set of brain regions which support the capacity for PM performance.

Age-related PM decline is observed across both Time- and Event-based components [24]. Notably, however, Time-based PM appears disproportionately disrupted relative to Event-based tasks in healthy older adults [24], suggesting that Time-based PM is a more cognitively difficult endeavor, potentially due to its greater dependence on self-initiated retrieval processes [24]. Compromised PM performance represents one of the most pervasive forms of memory disturbance in dementia and is viewed by caregivers as more disruptive than retrospective memory failures [25]. PM dysfunction is consistently demonstrated irrespective of dementia syndrome, with difficulties reported in Parkinson’s disease patients with cognitive impairment [26] and in amnestic and dysexecutive subtypes of mild cognitive impairment [27]. In addition, while impairments of retrospective episodic memory are considered to be a characteristic feature of AD [1], a number of studies suggest that PM failures occur at least as frequently in this population and are as severe [25]. Given that PM difficulties are evident inpreclinical AD and in very mild AD [28], substantial PM decline may be an early indicator of dementia [29].

To date the vast majority of studies of PM have focused on its disruption in MCI and AD [reviewed by 30], however, a recent study demonstrated marked PM dysfunction in bvFTD. Striking deficits were observed across Time- and Event-based forms of PM, with bvFTD patients scoring in line with disease-matched cases of AD [31]. These PM impairments were suggested to reflect potentially divergent underlying cognitive processes in each patient group; however, the underlying neural substrates of these deficits were not explored.

The present study represents the first investigation of the neural correlates of PM disruption in AD and bvFTD syndromes. Given converging evidence pointing to dissociable neural substrates of episodic memory disruption in AD versus bvFTD [6, 7], we predicted that unique neuroanatomical correlates of PM dysfunction would emerge in each patient group. Specifically, we hypothesized that a distributed network of frontal, medial temporal, and parietal regions would be implicated in AD, whereas predominantly anteromedial temporal and prefrontal regions would be involved in bvFTD. Importantly, given mounting evidence pointing to the involvement of the hippocampus in the genesis of episodic memory dysfunction in bvFTD [6, 32], we predicted that the hippocampus would represent a common neural correlate across the two disease syndromes.

METHODS AND MATERIALS

RESULTS

DISCUSSION

This study represents the first investigation of the neural correlates of PM dysfunction in the neurodegenerative disorders of AD and bvFTD. On a behavioral level, our findings reveal marked PM disruption across the patient groups, with Time-based PM disproportionately affected in AD relative to bvFTD participants. Notably, the integrity of episodic memory emerged as a key modulator of performance irrespective of PM subtype in bvFTD, and for Event-based PM disruption in AD. This observation was corroborated on the neural level with the hippocampus emerging as a common region implicated irrespective of group or PM task. Interestingly, levels of motivation were also found to modulate Event-based PM performance in bvFTD, while the mechanisms underpinning Time-based disruption in AD remain unclear. Our findings demonstrate that while commonalities exist in the neural substrates of PM dysfunction in AD and bvFTD, discrete neural systems underlie PM dysfunction in each group. Here, we discuss the implications of our findings for understanding PM dysfunction in dementia syndromes.

The present findings converge with a growing body of evidence pointing to significant episodic memory dysfunction in bvFTD extending across laboratory [6, 11], autobiographical memory [5] and sourcememory [54, 55] tasks. Notably our findings corroborate a previous study in which marked PM impairments were observed in bvFTD across both Time- and Event-based PM subscales [31]. Importantly, here we demonstrate that episodic memory processes significantly modulate the capacity for PM performance, irrespective of PM domain, as controlling for delayed episodic recall significantly ameliorated PM deficits in the bvFTD group. General levels of motivation, as measured on the CBI, were also found to significantly influence Event-based PM performance in bvFTD suggesting that the origin of Event-based disruption is multifactorial. As such, difficulties in retrieving the to-be-remembered information, coupled with increased levels of apathy characteristically seen in this syndrome, represent the chief candidate cognitive mechanisms driving PM impairments in bvFTD. The interplay between apathy and episodic memory processes in bvFTD remains underexplored and it will be important to determine how loss of motivation impacts the capacity to encode, store and retrieve new information in this syndrome.

Our proposal of a central role for episodic memory processes in PM disruption in bvFTD was confirmed on the neuroanatomical level with the hippocampus consistently implicated irrespective of PM subtask in this syndrome. Hippocampal atrophy is well documented in bvFTD [32] and has been shown to correlate robustly with episodic memory dysfunction in this group [6]. Accordingly, compromised PM performance in bvFTD may reflect disruption of the retrospective memory search processes required to retrieve the intended action, a process which is mediated by the hippocampus [56]. Notably, for Time-based PM performance, predominantly left-lateralized regions including the temporal fusiform cortex, parahippocampal gyrus, inferior temporal gyrus, and temporal pole were implicated, reflecting a predominantly anteromedial system, largely implicated in episodic memory performance, that is compromised in bvFTD [6].

PM performance is typically conceptualized as a frontally-mediated function [16], and impairments in this domain in bvFTD would ostensibly be viewed as relating to frontal lobe degeneration. Interestingly, we found significant involvement of the left orbitofrontal cortex albeit exclusively on the Time-based task in bvFTD. Lesions to the orbitofrontal cortex are associated with impulsivity and alterations in time perception [57] leading to a profound myopia for the future [58]. As such, Time-based PM deficits in bvFTD may, in part, stem from an impaired capacity to accurately perceive time, and indeed temporal processing difficulties are present in this disorder [59]. Time perception therefore represents a particularly interesting line of enquiry in light of recent findings revealing marked impairments in the ability to successfully project forwards to envisage the future in bvFTD [reviewed by 60]. Notably, future thinking deficits in bvFTD are attributable to atrophy in the right hippocampus and right frontopolar regions [61], underscoring the role of prefrontal and medial temporal lobe interactions in supporting future-oriented memory processes.

While the neural substrates of PM dysfunction in bvFTD resided predominantly in anteromedial brain regions, a more widespread network was implicated in the AD group. Unsurprisingly, AD patients displayed marked deficits irrespective of PM subscale, however, Time-based PM appeared disproportionately disrupted relative to the bvFTD group. Notably, this profile of PM deficits in AD did not merely reflect a general decline in cognitive functioning, as the same overall pattern of results persisted despite controlling for level of cognitive function using the ACE-R. Interestingly, Event-based PM deficits were ameliorated when we controlled for delayed verbal episodic retrieval processes, replicating our finding in the bvFTD group and pointing towards a common underlying cognitive mechanism driving Event-based PM disruption in both dementia subtypes.

The genesis of Time-based disruption in AD, however, remains unclear, as our covariate analyses failed to reveal a distinct modulator of this form of PM disruption. Disorientation to time is a hallmark clinical feature of AD [1] and it has been suggested that such temporal confusion relates to the degeneration of pathways connecting the hippocampus with posterior parietal structures [62]. Our voxel-based morphometry analyses support the involvement of the hippocampus and parietal regions, such as the angular gyrus, within a distributed network of other frontal, lateral temporal, and occipital regions. A number of studies point to the potential role of the frontal poles in supporting the capacity for time estimation [22, 63] and it is interesting in this regard that the bilateral frontal poles were also implicated in the AD group. Given that Time-based PM tasks require the individual to predict the future time point at which a response should be enacted, it has been proposed that frontopolar involvement might reflect the capacity to envisage one’s future behavior [22]. Notably, simulation of future events and information is grossly compromised in AD [64] with frontopolar regions strongly implicated in these deficits [65]. Accordingly, atrophy in frontopolar regions in AD may disrupt a time perception mechanism that is central to all forms of future-oriented thinking, including PM and future simulation. While we did not explore the contribution of time perception to PM performance in this study, systematic investigation of the interplay between these processes in the dementias is warranted. Further, we did not determine the capacity for patients to accurately read, or indeed remember, the specified times during the Time-based PM trials. Given that deficits in clock reading are prominent in AD [66], use of a clock as an external aid on PM tasks may not prove as effective as Event-based cues such as an alarm, culminating in the differential PM profiles observed here.

In keeping with previous studies of episodic memory dysfunction in AD [6, 7], we also found significant parietal involvement underpinning PM deficits in AD. Activation of parietal regions such as the angular gyrus and supramarginal gyrus, in concert with the prefrontal cortices, is consistently reported in functional neuroimaging studies of PM performance in healthy individuals [18]. These sites form part of a broader cognitive control network, which supports sustained attention and goal-directed cognition, as well as a range of cognitively demanding tasks such as planning and problem-solving [67]. Recent studies indicate that disruption of this frontoparietal cognitive control network in AD adversely impacts episodic memory performance [68]. Our finding of bilateral angular gyri involvement irrespective of PM subtype in AD is therefore notable. While the precise functions of the angular gyrus remain unclear, degeneration of this region in AD may disrupt the integration of information and imparting of meaning towards an intended action [69]. Our findings resonate with the conceptualization of PM as lying at the interface between the domains of memory and attention, with successful PM performance requiring a shift between external stimuli (e.g., cues) and representations of intentions stored in memory [18]. While the precise neurocognitive mechanisms driving Time-based PM deficits in AD remain unclear, our behavioral and neuroimaging analyses underscore the multifactorial nature of PM dysfunction in AD, likely reflecting the deterioration of episodic memory, compromised time perception mechanisms, and disruption of core cognitive control processes.

Finally, our neuroimaging analyses revealed the involvement of the lateral occipital cortices and occipital poles across Time- and Event-based forms of PM in AD. The exact role of occipital regions in PM, and indeed in general episodic memory, remains to be elucidated, however, it is notable that lesions involving occipital regions are associated with gross impairments in retrospective and prospective memory [70]. It has further been suggested that occipital cortical regions may support cue encoding during PM tasks [18, 23]. It will be important for future studies to delineate the contribution of these regions in order to understand how occipital atrophy in AD impacts PM performance.

The clinical implications of our findings are important when we consider the pervasive nature of PM disruption across dementia syndromes. PM is crucial for the successful execution of many everyday tasks essential for functional independence, for example, remembering to take medication, or to turn off the stove after cooking. In the context of dementia patients who are characterized by marked functional impairments, deficits in PM are particularly disquieting and may further contribute to decline in independent activities of daily living, difficulties with financial management, and poor medication adherence [13, reviewed by 14]. Our covariate analyses point to a central role for episodic memory processes in Time- and Event-based PM dysfunction in bvFTD, and Event-based PM in AD. Interestingly, during testing it was observed that the patients did typically respond to the occurrence of the Event-based cues, suggesting that our findings do not reflect a detection problem per se. For example, patients would note and respond to an alarm (one of the Event-based cues signaling that the planned action was to be executed) by pointing out that the alarm had gone off. Nevertheless, they did not give an indication that the alarm signified anything of importance. Thus, it appears that the significance of the cue is lost in dementia suggesting that Event-based impairments reflect, in part, a breakdown in the association between cue and action. Alternatively, increased levels of apathy in bvFTD may render the patient indifferent to such external cues.

A number of methodological limitations warrant consideration. Firstly, our sample size is relatively small, and it will be important to replicate our findings in a larger sample. The PM task we used in this context, although sensitive to PM deficits in AD and bvFTD, arguably lacks ecological validity in terms of the type of difficulties that dementia patients might experience in their everyday lives. Future studies of PM in dementia using more ecologically valid measures will be essential to clarify how the deficits we report here manifest in the everyday environment of the individual. In addition, while the PM task is highly sensitive to memory dysfunction in AD and bvFTD, it is important to note that the task affords low specificity in terms of diagnostic utility. The disproportionate disruption of Time-based PM in AD relative to bvFTD warrants further investigation, as the mechanisms driving this impairment in AD remain unclear. While the AD patients were more cognitively impaired relative to the bvFTD group on a number of cognitive screening tasks, covarying for overall levels of cognitive functioning did not alter our main findings. It may be, however, that the Time-based PM task is more cognitively demanding than the Event-based subscale, as healthy Controls tended to perform higher on the Event-based task. In addition, we did not counterbalance the order of Time- and Event-based conditions in this study and it remains unclear how the use of our distraction task (identifying humor from cartoon scenes) could potentially influence PM performance. These methodological issues speak to the complexity of PM assessment using traditional pencil and paper tasks, and we suggest that future studies exploring PM in dementia should ensure that Time- and Event-based PM subscales are matched in terms of task difficulty and scoring. Finally, we did not ask patients to describe the approach they took to complete the task, particularly whether they relied on any compensatory techniques, and they were not asked to rate their experience of PM disruption on this task or in their daily lives. It would be interesting to ascertain whether the striking PM deficits observed on the experimental task used here correlate with subjective reports of PM dysfunction, or whether loss of insight which emerges in dementia syndromes alters awareness of PM deficits.

In conclusion, this study represents the first investigation of the neural substrates of PM dysfunction in AD and bvFTD. Our findings, while preliminary, suggest that episodic memory dysfunction and loss of motivation contribute to PM deficits in bvFTD, with the hippocampus emerging as a key region in this process. In AD, episodic memory dysfunction underpins Event-based PM deficits however the processes driving Time-based PM disruption remain elusive and reflect the degeneration of a distributed network of regions in the brain. Our findings highlight the multifaceted nature of PM disturbance in dementia syndromes and point to the need for further work in this area to develop targeted remediation strategies to improve functional independence in the patient’s daily life.