Neuropsychol Rev DOI 10.1007/s11065-011-9172-z
REVIEW
Prospective Memory Impairment in Mild Cognitive Impairment: An Analytical Review Alberto Costa & Carlo Caltagirone & Giovanni Augusto Carlesimo
Received: 13 December 2010 / Accepted: 30 June 2011 # Springer Science+Business Media, LLC 2011
Abstract Mild cognitive impairment (MCI) is a heterogeneous condition characterized by the presence in an otherwise healthy elderly individual of cognitive deficits involving specific domains in the absence of significant functional impairments. Reports indicate that prospective memory (PM), that is, the ability to remember to execute delayed intentions, is impaired in individuals with MCI. The present review discusses the current debate in the literature on PM functioning in MCI by focusing on the relationship between prospective retrieval and retrospective memory functioning. Analysis of the reported evidence revealed that both the prospective component and the retrospective component of PM can be impaired in MCI. Declarative memory dysfunction may account for the retrospective memory impairment, while either reduced executive abilities or a deficit of reflexive mechanisms could explain the prospective component impairment. Keywords Mild cognitive impairment . Prospective memory . Episodic memory . Executive functions . Dementia
Overview: Mild Cognitive Impairment Due to the increase in population aging throughout the world, dementia has become a very pertinent topic A. Costa (*) : C. Caltagirone : G. A. Carlesimo I.R.C.C.S. Fondazione Santa Lucia, Via Ardeatina 306, 00179 Rome, Italy e-mail:
[email protected] C. Caltagirone : G. A. Carlesimo Clinica Neurologica, Università di Roma “Tor Vergata”, Rome, Italy
for clinical neuroscientists. In a recent paper entitled “Alzheimer’s disease: a global challenge for the 21st century”, Dartigues (2009) reviewed epidemiological data indicating that cases of dementia will increase exponentially over the next 40 years and will involve about 115 million individuals by 2050 (Wimo et al. 2003; see for similar estimates Ferri et al. 2005). And, although a great deal of research has been carried out in recent years, the currently available treatments for dementia are largely ineffective. One important factor in this regard is the difficulty of testing and implementing therapies early in the disease course. This is due to objective difficulty in defining and identifying the preclinical and prodromal signs of the brain pathologies responsible for dementia, also due to the relative low sensitivity and specificity of psychometric measures in distinguishing between very early cognitive decline in patients who are developing AD and mild cognitive changes prodromal of other dementing and non dementing conditions of the elderly (e.g., depression, mild vascular disease, etc.). Interest in the concept of mild cognitive impairment (MCI) takes place within this scientific and cultural context. MCI is conceived as a borderline condition between healthy aging and dementia; it is characterized by the presence, in an otherwise healthy elderly individual, of a cognitive deficit perceived as a significant decline by the individual himself or by a family member and is objectively documented by scores below the norm on psychometric tests (Petersen 2004). In this context, it has been recently shown that, in addition to more traditionally investigated neuropsychological deficits (e.g., episodic memory, executive functions, visuo-spatial and linguistic abilities), individuals with MCI may present with significant reduction of prospective memory (PM) functioning that, in general terms, refers to the ability to remember to carry-out previously planned actions.
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Since Petersen et al. (1999) proposed that MCI is a nosographic entity, notions about the condition have been revised and updated. In fact, MCI is no longer considered a homogeneous condition but rather a syndrome encompassing a variety of disorders that share the above-mentioned diagnostic criteria but that differ substantially in terms of etiopathological and phenotypical characteristics. In particular, current views classify different sub-types of MCI according to an algorithm that considers the presence/ absence of a declarative memory deficit as a key sign. Therefore, individuals with MCI are recognized as amnestic (aMCI) or non-amnestic based on the neuropsychological demonstration of a deficit involving declarative memory or other cognitive functions, respectively (Petersen 2004). A further subdivision in MCI is made based on the presence of deficits implicating a single cognitive domain or, alternatively, more than one cognitive domain. Accordingly, both in amnestic and non-amnestic MCI single domain and multiple domain conditions can be distinguished (Petersen 2004). The practical relevance of distinguishing different MCI subtypes is related to the idea that they might represent the prodromal phase of different pathological conditions (Tschanz et al. 2006). Indeed, follow-up studies revealed that multiple domain aMCI has the highest probability to progress to AD. Depending on length of follow-up, the rate of conversion to dementia was about 25% in single domain aMCI but it ranged between 54% and 77% in multiple domain aMCI (Bozoki et al. 2001; Alexopoulos et al. 2006). Moreover, likely indicating reduced conversion detection sensitivity in the amnesticonly subtype and tendency for isolated memory problems to be secondary to a host of temporary or psychiatric conditions, in single domain MCI (both amnestic and nonamnestic subtypes) a return to normal state is more frequently observed (Aretouli et al. 2011; Forlenza et al. 2009). Some authors also suggested that multiple domain aMCI may have a greater likelihood of representing a mixture of AD and other dementia-related pathologies (Petersen and Negash 2008).Unfortunately, studies that tried to confirm the predictive value of MCI subtype classification in the subsequent development of full-blown dementia reached inconsistent results. First, dementia is not invariably preceded by a condition that can be classified as MCI (Palmer et al. 2008). Moreover, results of some studies documented that MCI may improve and even disappear over time (Manly et al. 2008; Matthews et al. 2008; Nordlund et al. 2010; Perri et al. 2009), indicating that the presence of MCI does not invariably represent the early phase of dementia. Thus, research is now focused on identifying neurobiological or cognitive markers that more reliably predict dementia in individuals with MCI and, more specifically, the disease underlying the dementia syndrome.
Due to the much higher prevalence of AD than other pathological conditions in dementia, most of this research has focused on predictive indexes of AD development. Thus, for example, Mattsson and colleagues (2009) recently demonstrated that at baseline MCI patients who developed AD within a follow-up period ranging from 2 to 11 years had lower cerebrospinal fluid levels of Aβ42 and higher levels of both phosphorylated and total tau protein than healthy matched individuals and MCI patients who developed other forms of dementia (see also Landau et al. 2010). Likewise, some neuroimaging studies indicate that in individuals with aMCI decreased hippocampal volume may be a potentially interesting predictor of progression to AD (Jack et al. 1999, 2010; Wang et al. 2006). In this vein, Albert et al. (2011) propose a revision of clinical and research criteria for the individuation of MCI individuals with high or low likehood to suffer from underlying AD pathology, that takes into account the above neurobiological parameters. A great effort is also being made to clarify the characteristics of the memory impairment profile that distinguish MCI patients with impending AD from other MCI patients. In a series of papers, Perri et al. (2007a, b, 2009) demonstrated that severity of the impairment detected at the baseline observation on various indexes of declarative memory (i.e., learning, forgetting and recognition) progressively increased passing from individuals who at the two-year follow-up had completely normalized their cognitive performances (reversible MCI) to individuals who during the same time interval still fulfilled the diagnostic criteria for MCI (stable MCI) and, finally, to individuals who in the meantime had converted to AD. From a qualitative point of view, among the various attempts to differentiate the characteristics of the memory impairment in MCI individuals who progressed to AD as opposed to individuals who did not progress to AD, the neuropsychological criteria for the diagnosis of AD proposed by Dubois et al. (2007) must be mentioned. According to these authors, since preclinical AD is characterized by the neuropathological involvement of mesio-temporal structures (Braak and Braak 1991), the memory deficit in MCI individuals who will convert to AD presents the typical characteristics of the hippocampal amnesic syndrome. In particular, since the critical impairment in these patients is a deficit in consolidating new memory traces, the studied information will be unavailable to them regardless of whether the memory procedure provides or does not provide for either elaborative encoding or strategic retrieval or both. Initial support for this hypothesis was provided by Sarazin et al. (2007) in a study which confirmed that the conversion to AD of individuals with aMCI was predicted best by performance on a memory procedure providing support for both encoding
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and retrieval than by a more traditional, unassisted memory test (see Carlesimo et al. 2011, for a critical review of this literature). Since quantitative and qualitative analysis of memory disorders is crucial for the differential diagnosis of MCI and dementia (Dubois et al. 2007), it is surprising that so few studies have investigated prospective memory functioning in MCI. In the present review, after a brief presentation of the PM construct, we will discuss the results of studies that investigated PM functioning in individuals with MCI. In particular, we will focus on the qualitative characteristics of their PM impairment to provide an interpretation of existing data in terms of the cognitive processes involved.
Prospective Memory: A Definition PM is the cognitive ability that allows us to remember to execute delayed intentions. Interest in the PM construct began in the field of cognitive psychology and only recently became a relevant topic in the field of clinical neuropsychology. A prototypical PM paradigm requires subjects to execute some actions at the occurrence of a specific stimulus in the environment (event-based PM) or at the expiration of a specified time (time-based PM), while the subject is engaged in an ongoing, attention demanding activity. This paradigm is meant to resemble as closely as possible the ecological situation in which we are usually engaged in a number of activities in the time period intervening between the formation of the intention to do something in the future and the concrete realization of that intention. According to Einstein and McDaniel (1990, 1996), two distinct PM components, which rely on at least partially different cognitive mechanisms, concur in the performance of a PM task: i) the retrospective component, which is responsible for the initial encoding and long-term retention of the content of the intention (i.e. the specific actions to be performed) and of the target event or time triggering the realization of the intention (associative cue) and ii) the prospective component, which refers to the ability to autonomously activate the intention at the right moment (occurrence of the event or time elapsing) without any explicit prompt to recall being given. Indeed, a critical difference between PM and declarative memory tests is that in the latter the examiner prompts the experimental subject to initiate retrieval of the studied items, whereas in the former when the event occurs or the time expires the experimental subject has to rely exclusively on his own initiative to perform the intended actions. It is generally acknowledged that executive and declarative memory abilities are differently implicated in the two PM components. Indeed, the encoding and long-term
retention of the associative relationship between a specific event or time and the concrete actions to be performed requires correct functioning of the declarative memory system. Conversely, the executive system is mainly implicated in the control of a number of mental operations needed to spontaneously activate the prospective intention at the appropriate time or at the occurrence of the target event. In fact, since performing a PM task is typically embedded in an ongoing, attention consuming activity, subjects need to share their cognitive resources between performing the ongoing task and keeping track of the PM task (e.g., by periodically reminding the prospective intention, actively monitoring the external environment, checking the passing of time, etc.). Moreover, at the appropriate moment (i.e. at the occurrence of the critical event or time), they must stop performing the ongoing task and begin performing the intended action. Top-down attentional control, strategic monitoring of the external environment and/or of the time passing and shifting between concurring activities are all cognitive abilities under the control of the executive system (Knight 1998; Burgess and Shallice 1997; Carlesimo et al. 2004; Marsh et al. 1998; McDaniel et al. 1999; McFarland and Glisky 2009; Otani et al. 1997) (Fig. 1). However, the active role of the executive system to coordinate the multiple cognitive operations needed to perform the ongoing task and not to miss the target event that triggers recall of the prospective intention might not be critical for all PM tasks. McDaniel et al. (2004) proposed that, depending on the specific experimental conditions, retrieval of the prospective intention in an event-based PM task may be underpinned by different cognitive processes, which they term reflexiveassociative and cue-focused, respectively. According to these authors, the relative contribution of these two processes to performance of an experimental PM paradigm can be manipulated by varying the association between the prospective cue and the actions to be performed, the salience of the cue with respect to the relative context and the way in which the ongoing task encourages or not processing of the attributes of the target event that were processed during initial encoding (focal and unfocal PM paradigms). In fact, when the target event is highly associated with the action to be performed, it is salient with respect to the stimuli processed in the ongoing task or it is in the focus of the ongoing task (e.g., it is represented by a particular word during an ongoing task in which subjects have to decide whether one word is a member or not of a specific category), the subject might rely mainly on automatic processes to recall the prospective intention at the appearance of the prospective cue; in the opposite condition, that is, low association between cue and action, low cue salience and unfocal cue (e.g., target stimulus represented by a particular word during an ongoing task in
Neuropsychol Rev Fig. 1 Schematic illustration of PM components and cognitive processes involved in a PM task
which subjects have to decide whether one word contains or not a specific syllable), strategically driven, cue-focused processes should be implemented to detect the target stimulus and to recall the associated prospective intention (McDaniel et al. 2004; McDaniel and Einstein 2010). From a neurobiological perspective, involvement of the declarative memory processes and executive abilities in the retrospective and prospective components of a PM task, respectively, suggests that the same neural circuits involved in declarative memory and executive functions might also be critical for the correct functioning of PM. More specifically, the hypothesis can be advanced that the mesio-temporal structures and interconnected cortical and subcortical areas involved in normal declarative memory functioning (Eichenbaum 2006) are also responsible for the normal functioning of the retrospective component of PM. Conversely, the prefrontal cortical areas, whose role in the neural control of executive abilities is well known (Owen 1997), should also be implicated in the normal functioning of the prospective component of a PM task. Consistent with this general hypothesis, convergent findings from the neuropsychological analysis of brain-damaged individuals and functional neuroimaging and neurophysiological investigations of healthy subjects indicate that mesio-temporal cortical areas (Adda et al. 2008; Poppenk et al. 2010) and the connected thalamic nuclei (Carlesimo et al. 2011) should be more involved in modulation of the retrospective remembering. Conversely, prefrontal cortical areas are particularly involved in modulating the ability to autono-
mously retrieve the intention (Bisiacchi et al. 2009; Burgess 2000; Burgess et al. 2003; Simons et al. 2006; Poppenk et al. 2010). Within the prefrontal cortex, a specific involvement of the frontal pole in the prospective component of PM processes has been proposed (Burgess et al. 2001, 2003; Costa et al. 2011a; Simons et al. 2006). In particular, functional neuroimaging studies strongly document that neurons in the lateral and mesial portions of Brodmann area (BA) 10 underlie cognitive processes necessary for both prospective intention maintenance/retrieval and detection of the prospective cue triggering PM response (e.g., Burgess et al. 2003; Simons et al. 2006). A clear cut implication of BA 10 in the modulation of PM mechanisms has been recently demonstrated by the results of a study from our laboratory (Costa et al. 2011a). In that study, involving a group of young healthy individuals, we provided the first demonstration that the transient alteration of the neuronal activity within BA 10 by means of the deliverance of transcranial magnetic stimulation (i.e., continuous theta burst stimulation) significantly affects the PM response accuracy. There is a general consensus that a PM deficit may have a significant impact on the functional autonomy of the affected individual (Kliegel et al. 2011; Smith et al. 2000). For instance, the ability to realize future projects or simply keep an appointment, pay a bill, or remember to take medicine are a few of the activities that might be seriously impaired by a failure of PM processes. However, the relationship between PM deficits, as detected by a
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standardized clinical assessment, and the occurrence of PM failures in the real life is not linear. By a way of an example, some studies document that aged healthy individuals, in respect to young subjects (under thirty in most of the studies), are more likely to achieve poorer PM performance on “laboratory” tasks whereas they could even outperform younger subjects on naturalistic measures (Henry et al. 2004; Phillips et al. 2008). This effect, named age-PM paradox, is detectable even when highly ecological tests are used to evaluate PM in a laboratory setting (e.g., Rendell and Craik 2000). To account for such a phenomenon, it has been claimed that older adults could be more motivated to attain to PM instructions in real life situations than younger adults, that external memory aids may be available at a greater extent in real life and that laboratory settings may be more time-stressful than naturalistic ones. In a recent review, McDaniel and Einstein (2011) propose an alternative approach to clarify the characteristics of age related changes in PM functioning. In the authors view, based on the assumptions that i) frontal lobes are particularly involved in the mediation of PM and that ii) prefrontal areas are vulnerable to aging, the PM decline would be detectable specifically by PM paradigms that stress the involvement of frontal related functions (e.g., strategic monitoring, working memory, planning). This hypothesis is supported by experimental data showing that older adults’ performance are not significantly worse than those of young individuals in PM paradigm that support spontaneous retrieval (i.e., focal PM task), while they achieve poor scores on those tasks that are highly demanding in terms of planning and strategic resources (i.e., un-focal PM tasks; Kidder et al. 1997; McDaniel and Einstein 2007; Park et al. 1997; Scullin et al. 2011). PM deficits are associated with self-rated memory problems even more frequently than retrospective memory disorders (Kinsella et al. 1996) and they are a relatively common features in various neurological populations. Indeed, a significant decline in PM performance has been documented in individuals suffering from the long-lasting consequences of severe head trauma (Carlesimo et al. 2004; Groot et al. 2002; Henry et al. 2007; Tay et al. 2010), Parkinson’s disease without dementia (Katai et al. 2003; Kliegel et al. 2005; Costa et al. 2008a, b), epilepsy (Adda et al. 2008), thalamic stroke (Carlesimo et al. 2011), and focal lesions involving the prefrontal cortex (Burgess 2000). Early impairment of PM has been observed in AD (Huppert et al. 2000; Maylor et al. 2002) and data from a previous study demonstrated that failure on a PM task was more accurate than traditional tests of retrospective memory in discriminating between persons in the very early stage of dementia and healthy subjects (Huppert and Beardsall 1993). Available findings also indicate that PM is pervasively impaired in individuals with both amnestic and non-
amnestic MCI; therefore, PM may be a relevant topic to explore in this population.
Prospective Memory Functioning in MCI In the last few years, eight papers have been published that report the performance of individuals with MCI on PM tasks. A deficit of declarative memory was the most frequently documented cognitive impairment in the reported patients. In particular, the MCI samples investigated by Kazui et al. (2005), Costa et al. (2010), Karantzoulis et al. (2009), Thompson et al. (2010), and Troyer and Murphy (2007) included single domain amnestic individuals. Some studies also included individuals with memory deficits associated with other cognitive deficits (i.e., multiple domain amnestic) and/or non-amnestic MCI (Costa et al. 2011b; Schmitter-Edgecombe et al. 2009; Thompson et al. 2010). Finally, only one subgroup of patients reported by Costa et al. (2010) suffered from an isolated executive deficit with substantially spared memory functions. In general, most evidence emerging from these studies indicates that in individuals with MCI PM abilities are significantly reduced compared with matched, healthy, aged persons. In the first study, Kazui et al. (2005) administered the Rivermead Behavioural Memory battery to a group of individuals with single domain aMCI. This instrument includes measures of both declarative memory and event-based PM. The authors reported that the aMCI subjects’ performance was equally reduced on both kinds of memory tasks. Subsequent research, including both laboratory-based experimental procedures (Blanco-Campal et al. 2009; Costa et al. 2010; Schmitter-Edgecombe et al. 2009) and more ecologically oriented paradigms (Karantzoulis et al. 2009; Troyer and Murphy 2007; Thompson et al. 2010), substantially replicated the finding of significantly decreased PM functioning in MCI individuals. In reviewing this literature, we will take into account the neurocognitive model proposed above, which distinguishes the contribution of relatively independent prospective and retrospective components to overall performance on a PM task. In view of the basic declarative memory deficit that characterizes the cognitive impairment in most MCI individuals reported in these studies, the main hypothesis to be verified is that the PM impairment in these patients was mainly underlain by a deficit of the retrospective component. Furthermore, since many of the reported MCI individuals also suffered from a dysexecutive syndrome (which in a few cases was the only documented cognitive deficit), the possibility that impairment of the prospective component also contributed to the overall PM deficit merits consideration.
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Retrospective Component Failure in the PM Performance of MCI Patients Karantzoulis et al. (2009) administered the Memory for Intentions and Screening test (Raskin 2004) to 27 individuals with single domain aMCI and 27 healthy controls. During the test, subjects had to complete eight time- and event-based PM tasks with various delay intervals. The ongoing activity consisted of performing word search tests. In the time-based tasks, subjects were required to execute a prospective action (e.g., to remind the examiner to make something) after 2 min. or 15 min. In the event-based condition, the subjects had to retrieve the intention upon presentation of a specific object. To evaluate whether PM failures might be due to a lack of declarative memory for the target event or time and/or specific actions to be made (retrospective component), at the end of the PM task they had to explicitly recall the test instructions. The results of the study showed that individuals with MCI performed less accurately than healthy controls on both prospective retrieval and recollection of the prospective instructions. More importantly, although aMCI individuals tended to make more omission errors than healthy controls, thus suggesting a greater involvement of prospective than retrospective memory, the examination of the relationship between omissions and performance on the subsequent recognition task revealed that subjects belonging to both the aMCI and healthy control groups were more likely to make retrospective than prospective errors. The findings by Karantzoulis et al. (2009) clearly emphasize the strict relatedness between PM functioning and retrospective memory processes in the examined individuals. A recent study by Thompson et al. (2010) was specifically devised to investigate the contribution of prospective and retrospective components to overall performance on a PM task. The authors administered a revised version of the Virtual Week, a computerized board game representing the activity of a typical day (which constitutes the ongoing activity) to individuals with both amnestic (n= 20) and non-amnestic forms (n=28) of MCI. MCI subjects achieved lower scores than controls on both the prospective and retrospective (recall and recognition measures) components of the task. Moreover, a subsequent analysis of the covariance documented that a significant proportion of the deficit disclosed by MCI individuals on the prospective component of the task was actually accounted for by their poor performance on the retrospective component. Results of the study revealed no significant difference in PM performance in MCI individuals with different neuropsychological profiles. Two recent studies carried out in our laboratory using different experimental procedures attempted to disentangle the different weight of prospective and retrospective deficits
in the increase of poor PM performances in patients with amnestic and non-amnestic MCI. In the first study (Costa et al. 2010), we administered a time- and an event-based PM procedure, which required executing three unrelated actions (e.g., telling the examiner to turn off the computer; writing one’s name on a sheet of paper; replacing the telephone receiver) after 20 min. had elapsed or a timer had rung, to individuals with either single domain amnestic (n=10) or non-amnestic (i.e., dysexecutive; n=10) MCI. The PM procedure was expressly devised to obtain independent scores on the prospective and retrospective components of the PM task; the former was represented by the number of times the experimental subject autonomously retrieved the intention to perform the actions, and the second consisted of the total number of actions correctly recalled after controlling for failure to autonomously retrieve the intention. The overall group of MCI subjects (collapsing amnestic and non amnestic individuals) was significantly less accurate than healthy controls on both autonomous retrieval of the intention (prospective component) and recollection of the actions to be performed (retrospective component). In the second study, we more directly addressed the role of a retrospective memory failure in the overall deficit disclosed by MCI individuals on a PM task. In that study (Costa et al. 2011b), 24 aMCI subjects (17 single domain and 7 multiple domain) and 24 healthy matched individuals were administered an event-based PM task requiring experimental subjects to press a key at the appearance of a target word while they were engaged in an ongoing task in which they had to reproduce four-word sequences. The memory load of the PM task was manipulated by varying the number of target words (1 vs. 4); the attentional/ executive demand of the ongoing task was manipulated by requiring subjects to reproduce the word sequences forward or backward. Declarative memory for the target words (retrospective component) was evaluated using a free recall test at the end of each experimental block. We also calculated for each subject the accuracy at pressing the key button during the PM task separately for the words which at the end of each experimental block were recalled or not recalled. In the overall experimental sample (including both aMCI and NC participants) and across different experimental conditions, accuracy on the PM task was about 60% for the correctly recalled words but ranged between 4 and 15% for the words that were not recalled. This finding clearly demonstrates that memory of the target words is a necessary prerequisite for successful performance on the PM task. Accordingly, since aMCI individuals on average recalled significantly fewer target words than NC individuals (53% and 21% fewer words on the four-word and one-word conditions, respectively), their reduced performance on the PM task was at least partially underlain by their inability to remember the target words.
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Taken together, the results of these studies indicate that failure in retrospective remembering (interfering with either retrieval of the specific actions to be performed or recognition of the target events) significantly affects the PM performance of individuals with MCI. What remains to be clarified is whether the retrospective memory impairment of individuals with MCI fully accounts for their reduced accuracy in realizing delayed intentions or, instead, whether a failure of the prospective component also contributes to the overall deficit. To clarify this point, in the next section we will scrutinize the available literature for evidence that in addition to difficulty in consolidating declarative memories of the content of the intention and/or of the target event/time MCI patients also suffer from specific difficulty in autonomously reactivating the prospective intention (i.e., the prospective component of the PM task) even when the declarative memory of the intention is available. Prospective Component Failure in the PM Performance of MCI Patients Three lines of evidence support the hypothesis that reduced PM abilities in individuals with MCI cannot be attributed exclusively to a deficit of the retrospective component. Indeed, some data suggest that MCI patients: i) present a disproportionately more severe deficit on tests of PM than on tests of declarative memory, ii) fail to spontaneously activate the prospective intention despite normal declarative memory for the intention itself, and iii) are particularly impaired on those PM procedures in which contextual cues minimally support the intention retrieval. Two studies reported data in favor of a more severe deficit of MCI individuals on tests of PM than on tests of declarative memory. Blanco-Campal and colleagues (2009) administered two traditional declarative memory tests (a Short Paragraph and Word List recall) and an event-based PM test to a group of aMCI and a group of healthy controls. In the PM task, subjects were required to say aloud the word “animal” when they saw the name representing one only specific animal (e.g., subjects had to activate themselves only when the word “lion” was presented; specific condition) or when they saw a word indicating any type of animal (unspecific condition). In both conditions, the target words could be written in italics (salient target) or in a regular format (non-salient target). During the ongoing activity, they performed a lexical decision task. Results showed that the PM task had greater sensitivity (84%) and specificity (95%) in discriminating between MCI and normally aged individuals than all other traditional declarative memory tests administered (e.g., 83% and 76% sensitivity and specificity on the CERAD Word List Memory test). A more direct comparison of performance
on the retrospective and prospective components of a PM task was made in a study carried out in our laboratory. In that study (Costa et al. 2010; see above for a detailed description of the procedure), a comparison of z-scores computed on the basis of performance scores achieved by an healthy control group comparable as for age and education to the MCI sample, revealed that both amnestic and non-amnestic MCI subjects were more severely impaired on the prospective than on the retrospective component of the PM task. In fact, the number of MCI individuals who obtained pathological scores (i.e. a score 1.5 SD below the mean of the group of healthy controls) on the prospective component of the time-based task (n=17; 85% of cases) was significantly higher than the number of individuals who scored in the pathological range on the retrospective components of both the time- and event-based tasks (n=7; 35% and n=8; 40%, respectively). Published studies have also provided evidence that the failure rate of individuals with MCI to perform the intended action in a PM task is over and above their declarative memory impairment for the content of the intention itself. Schmitter-Edgecombe et al. (2009) investigated a wide spectrum of memory abilities, including activity-based PM (a kind of event-based PM in which the target event is represented by finishing an ongoing activity), in two groups of individuals with both amnestic (n=27) and non-amnestic (n=15) MCI and in one healthy control group (n=42). During the ongoing activity of the PM task, subjects were administered eight tests assessing a variety of cognitive functions and, at the end of each test, they were required to rate how much they liked it on a Likert scale. After they finished rating the test, they had to ask the examiner for a pill bottle (PM instructions). The authors reported that MCI subjects failed to retrieve the intention to act (prospective component) even though they were normally able to recall the PM instructions (retrospective component). Indeed, the individuals in both the amnestic and the non-amnestic group of MCI on average requested the medicine bottle significantly less than controls; but, no significant difference in PM performance was found between the two MCI groups. Thompson et al. (2010) tried to disentangle the contribution of the prospective and retrospective components by introducing the performance score obtained on the retrospective component as a covariate in the statistical model that compared the overall performance of a group of MCI patients and a group of healthy controls on a PM task. Results documented that MCI individuals were still significantly impaired in spontaneously retrieving the intended action even after correcting the declarative memory for the intention, thus demonstrating that failure in the retrospective component could not fully account for the reduced accuracy displayed in the prospective component. Finally, in one study (described above) carried out in
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our laboratory (Costa et al. 2011b), the item-by-item correspondence between declarative memory and autonomous activation of the intention was overall lower in the MCI than the control group. In the experimental condition, in which only one target word had to be remembered, the difference was statistically significant. Indeed, while healthy controls performed the expected action (pressing the response key) over 70% of the times a target word, which was eventually recalled, appeared, the PM accuracy of individuals in the aMCI group for the same kind of words was only 50%. This indicates that even when the target word was stored normally, it was less effective in eliciting the retrieval of the prospective intention in the MCI participants with respect to healthy controls. Finally, three studies reported evidence that the performance of MCI individuals was disproportionately affected by the executive demands of the PM tasks. Two of these studies documented more severe impairment of MCI individuals on time-based than event-based PM tasks. Troyer and Murphy (2007) administered an experimental procedure to a group of 45 aMCI subjects that required reporting the time to the examiner every 30 min (timebased condition), or using a pen of a particular color whenever they engaged in tasks requiring a writing instrument (event-based condition). They found that, within a global decrease in PM performances of patients with MCI compared to healthy controls, MCI patients had greater difficulty in performing the time-based compared with the event-based task. In the previously described study, Costa et al. (2010) also found that MCI individuals were more severely impaired on the time-based than the event-based task (i.e. they were 80% and 40% less accurate than normal controls, respectively). The particularly poor performance of MCI individuals on time-based PM tasks can be interpreted as due to the higher demands posed by this experimental condition on attentional and executive resources (Brandimonte and Passolunghi 1994; Einstein et al. 1995; Groot et al. 2002; Maylor et al. 2002; Park et al. 1997). Indeed, in a time-based task attention has to be continuously shifted from the ongoing task to time monitoring to self-activate the intention to perform the action at the appropriate moment (i.e., after the time has elapsed). In the event-based condition, this attentional charge is reduced because the occurrence of a precise event marks the right moment to perform the actions (i.e., occurrence of the prospective target). This constitutes a sort of “cue” facilitating recollection of the intention, i.e., an environmental support requiring less voluntary control and less attentional resource allocation than that necessary in the time-based condition (Brandimonte and Passolunghi 1994; Kvavilashvili 1987; Marsh et al. 1998; Otani et al. 1997). Results of the study by Blanco-Campal et al. (2009) are also in line with the assumption that performances of MCI
individuals on a PM task are particularly poor when the executive demands of the experimental paradigm are high. Indeed, results of the study demonstrated that the condition of the PM task which best discriminated between MCI individuals and controls was the one that required the most strategic monitoring for target stimulus detection (i.e., the unspecific, non-salient condition; see above for a detailed description of the procedure). Although the causal relationship between the impaired retrospective component and a deficit of the declarative memory system seems clear in MCI individuals, the cognitive dysfunction underlying failure in the prospective component is far less straightforward. As previously mentioned, executive functions, particularly planning, set shifting and strategic monitoring, are required for successful performance on the prospective component of a PM task (Burgess 2000). In fact, these abilities are reported to be impaired in subjects with MCI (Arnáiz and Almkvist 2003; Backman et al. 2005; Blacker et al. 2007; Chang et al. 2010). For example, Schmitter-Edgecombe and Sanders (2009) recently demonstrated that individuals with MCI present with a poor shifting attitude as they show a higher switch cost in the execution of two different tasks compared with healthy controls. In fact, the ability to shift from one task (or a mental representation) to another is critical in performing PM tasks. Data reported in the literature (and our data, in particular) are not univocal regarding the relationship between executive dysfunction and reduced ability to spontaneously activate the prospective intention in individuals with MCI. Overall, the results of our first study (Costa et al. 2010) were consistent with this hypothesis. Indeed, a direct comparison of the performance of the two groups (i.e. amnestic and dysexecutive MCI individuals) on our PM procedure revealed a double dissociation between performance on the prospective and retrospective components of the PM task. This finding was expected because of the different role played by executive and declarative memory functions in the two components. In fact, participants in the amnestic group were particularly poor in retrospective recall of the actions to be performed. For example, in the event-based condition these patients, but not those of the dysexecutive group, recalled significantly fewer actions than the group of healthy controls. Conversely, the dysexecutive MCI patients were more impaired on the prospective component of the PM task than the amnestic group. Although accuracy on the event-based task did not differ between the two groups, the dysexecutive individuals were significantly more impaired than the amnestic ones on the time-based task. Nevertheless, results of the second study (Costa et al. 2011b) provide less support for the notion that an executive impairment underlies the deficit of MCI individuals on the prospective
Neuropsychol Rev
component of PM tasks. First, in the MCI group there was no evidence of a significant correlation between accuracy of intention retrieval in the PM task and performance on tests tapping executive functioning (see also Karantzoulis et al. 2009 for similar data). Second, the deficit disclosed by MCI patients on the prospective component of the PM task was not modulated by the attentional/executive demands of the ongoing task. In fact, these patients were similarly impaired when the ongoing task request was to reproduce the fourword string forward or backward. The above discussed data seem to outline that although executive dysfunction may contribute to poor PM performance in MCI population, it alone does not completely account for the observed pattern. In line with this observation, an alternative explanation of this deficit rests on the hypothesis that, in physiological conditions, the successful fulfillment of a delayed intention may actually occur with a relatively low demand upon executive control. Here we are referring to the reflexive-associative mechanism posited by McDaniel et al. (2004) as opposed to cuefocused mechanisms that require the implementation of strategic voluntary processes. According to these authors, in experimental paradigms in which the PM target is the focus of the ongoing task, the target event and the action to be performed are highly associated and the target event is perceptually salient, the retrieval of the prospective intention (i.e., the intention to act) “pops into the mind” obligatorily, with relatively low demand on attentional/ executive systems. In these cases, the interaction between the cue event and the memory traces representing the intended action is critical for intention retrieval; and the strength of the action depends directly on the level of activation of the association between the target event and the intended action at the time of the intention encoding. Poor encoding of this association could make the target less efficient in triggering the action in MCI individuals. At least for aMCI individuals, it can be hypothesized that decreased efficiency of the declarative memory system might lead to failure in encoding the associative link between the target event and the expected prospective action, even for those events whose identity has been correctly encoded (Costa et al. 2011b; Karantzoulis et al. 2009). Further studies evaluating the effect of manipulating the characteristics of the encoding phase of the PM performance of MCI subjects are necessary to clarify this issue.
in a typical PM paradigm, PM responses are relatively rare (i.e., a PM response is required at the occurrence of less than 20% of total presented stimuli). Therefore, it may be the case that statistical analyses comparing the performance of different samples are executed on relatively restricted range scores. This could reduce the sensitivity of a PM task at highlighting significant between groups differences and, thus, should lead to cautiousness in interpreting negative data. Other main questions are represented by the heterogeneity of the PM paradigms used across studies (e.g., experimental paradigms vs. standard protocols; time-based vs. event-based tasks) as well as of the characteristics of patients recruited (amnestic or non amnestic MCI; single domain or multiple domain MCI), and methods to classify patients (clinical and psychometric criteria used for the MCI diagnosis). These latter factors, indeed, affect reliability of comparisons between different studies and the possibility to generalize the results to the whole MCI population. Intrinsic limits of some studies could also affect their conclusions. For instance, some of the evidence pointing to a more severe deficit in the prospective than the retrospective component of a PM task in individuals with aMCI (e.g., Costa et al. 2010; Schmitter-Edgecombe et al. 2009) could have been biased by the very low memory demands of the retrospective task. In this regard, it should be noted that only one study directly contrasted the prospective vs. retrospective PM components by manipulating the memory and attentional/executive demands of the two components of the PM paradigm (Costa et al. 2011b). Moreover, some data were obtained on non homogeneous MCI sample - e.g., Thompson et al. (2010) included both amnestic and non amnestic individuals and Schmitter-Edgecombe et al. (2009) did not differentiate between single and multiple domain MCI. This prevents from the possibility to clarify whether a pattern of PM impairment is specific to a certain aMCI subtype. A final critical aspect is represented by the low size of the MCI samples investigated. As reported in Table 1, the mean number of MCI subjects recruited by the existing studies is about 25, ranging from 10 (in the case of MCI subtypes classification) to 48 (in the case the MCI sample included different MCI subtypes). Indeed, the relatively low sample size could have reduced the power of statistical analyses thus possibly leading to overinterpretation of data.
Methodological Issues Relative to the Extant Literature on PM in MCI
Concluding Remarks and Future Directions
Some limits to the straightforward interpretation of data from PM literature on MCI should be considered. Overall,
This review of the literature confirms significant impairment of PM functioning in individuals with MCI. Furthermore, analysis of these data in light of a componential
15
aMCI (not specified)
aMCI single and multiple domain Non-amnestic MCI single and multiple domain aMCI and non amnestic MCI Single domain aMCI
Blanco-Campal et al. 2009 Schmitter-Edgecombe et al. 2009
aMCI single and multiple domain
24
10
10
48
27
45
72.7(7.1)
70.9(6.0)
73.5(5.7)
78.6(4.9)
71.0(5.6)
75.7(7.6)
75.8(6.7)
9.4(3.7)
10.3(3.2)
10.1(4.3)
12.2(3.9)
15.9 (n.a.)
21
≤13: n=16 >13: n=3 16.1(n.a.)
Experimental
Experimental
Virtual Week
Experimental
Experimental
MIST
Experimental
RBMT
PM test
*refers to the difference between MCI and healthy control subjects (in all cases MCI individuals
