Differential Prospective Memory Profiles in Frontotemporal Dementia Syndromes

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Journal of Alzheimer’s Disease 38 (2014) 669–679 DOI 10.3233/JAD-131118 IOS Press

Differential Prospective Memory Profiles in Frontotemporal Dementia Syndromes Jody Kammingaa , Claire O’Callaghana,b , John R. Hodgesa,b,c and Muireann Irisha,c,d,∗ a Neuroscience

Research Australia, Randwick, Sydney, Australia of Medical Sciences, The University of New South Wales, Sydney, Australia c Australian Research Council Centre of Excellence in Cognition and its Disorders, Sydney, Australia d School of Psychology, The University of New South Wales, Sydney, Australia b School

Accepted 3 August 2013

Abstract. Background: Prospective memory (PM) is the ability to remember to execute an intended action either at a future time (Timebased PM) or when a specific event occurs (Event-based PM). Previous studies demonstrate impaired PM in Alzheimer’s disease (AD); however, the status of PM in frontotemporal dementia (FTD) remains unknown. Objective: To examine PM performance and its associated cognitive mechanisms, in two subtypes of FTD: semantic dementia (SD) and the behavioral variant of FTD (bvFTD), in comparison with matched AD and control participants. Methods: Twenty-four dementia patients (SD = 8; bvFTD = 8; AD = 8) and 12 age- and education-matched controls underwent a shortened version of the Cambridge Behavioural Prospective Memory Test, as well as a standard neuropsychological test battery. Results: Compared to controls, SD patients exhibited preserved Time-based PM in the context of impaired Event-based PM, with the latter strongly associated with deficits in semantic processing. In contrast, bvFTD and AD patients demonstrated global PM impairments irrespective of subscale, which strongly correlated with deficits in delayed episodic retrieval for both groups. Caregiver reports of stereotypical behaviors were associated with compromised Event-based PM in SD and Time-based PM in bvFTD, with no such relationship evident in AD. Conclusion: This is the first study to investigate prospective memory in FTD syndromes. A relative sparing of Time-based PM was observed in SD, in contrast with global PM deficits in bvFTD. Disrupted PM processing was found to correlate with stereotypical behaviors in FTD syndromes, a finding that we suggest is worthy of further investigation. Keywords: Aging, alzheimer’s disease, behavioral variant frontotemporal dementia, episodic memory, neuropsychological tests, prospective memory, semantic dementia

INTRODUCTION Forgetfulness is a hallmark clinical complaint in dementia and is often one of the initial symptoms recognized by caregivers [1]. Such caregiver reports of everyday forgetfulness reflect the breakdown of prospective memory (PM), the process of remembering to carry out an intended action at an appropriate ∗ Correspondence to: Dr. Muireann Irish, Neuroscience Research Australia, Barker Street, Randwick, Sydney, NSW 2031, Australia. Tel.: +61 2 9399 1602; Fax: +61 2 9399 1047; E-mail: [email protected].

time in the future [2]. Unlike memory for past events (retrospective memory) where recall occurs following an explicit prompt from another individual, PM is self-generated, requiring the individual to ‘remember to remember’ [3]. While the quality of planning an intended action has been associated with PM performance in healthy older adults [4–5], PM is a multi-component process with planning forming one of the initial stages [2]. For PM to be successful, it also requires retrieving the action at the appropriate time or place, and execution of the action [2]. Various lines of evidence point toward the role of the frontal

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lobes in planning, strategic monitoring, and execution of PM, while medial temporal lobe involvement has been implicated in tasks that are more dependent on spontaneous or reflexive retrieval (see [2] for a review). A further distinction between Time-based and Event-based PM has been made [3]. Time-based PM involves remembering to execute an intended action at a specified time (e.g., remembering to go to a doctor’s appointment at 2 pm the following Monday), whereas Event-based PM requires remembering to perform an intended action when a specific event occurs (e.g., remembering to buy postage stamps the next time you are at the shops) [3, 6]. Greater difficulty has been documented on tasks of Time-based relative to Event-based PM in healthy older adults [7, 8] and in Parkinson’s disease patients without frank dementia [9]. This difference has been attributed to the increased effortful active rehearsal, attentional monitoring, and self-initiated remembering that is required in Time-based tasks [9–10]. In contrast, Event-based PM tasks have been regarded as more automatic, relying instead on the reflexive and spontaneous response to the appearance of an environmental cue to signal the appropriateness of an intended action. While disproportionate difficulty on Time- versus Event-based PM tasks has been reported in the dementia literature (e.g., [11]), evidence for this theoretical distinction remains equivocal. A recent meta-analysis [12] of several case-control studies demonstrated that overall, individuals with Alzheimer’s disease (AD) were impaired on both Event- and Time-based PM tasks relative to healthy age-matched controls. This global deficit irrespective of PM task has been interpreted as reflecting heterogeneity in task difficulty within Time- and Event- based PM tasks [12]. The finding of a global PM deficit in AD converges well with recent studies, such as that of Addis and colleagues [13], who reported significant impairments in patients with mild AD, irrespective of PM subscale (Time versus Event), on a modified version of the Cambridge Behaviour Prospective Memory Test [14]. Similarly, individuals with amnestic mild cognitive impairment (MCI) have been found to exhibit global deficits across Time- and Event-based PM [15], supporting the assertion that PM deficits arise in the pre-clinical stages of AD [16]. In both the pre-clinical and clinical stages of AD, it has been suggested that a global deficit in episodic memory processes underscores these difficulties in PM [12, 17]. To date, the majority of studies of PM in dementia have focused on AD, to the neglect of other syndromes such as frontotemporal dementia (FTD). FTD

is a progressive neurodegenerative disorder that is as prevalent as AD in the under 65 year age group, accounting for around 15 cases per 100,000 population aged 45 to 64 years [18]. Heterogeneous in its clinical presentation and underlying pathology, FTD encompasses a number of subtypes, the two best defined being semantic dementia (SD) and behavioral variant of FTD (bvFTD). SD, also known as semantic variant Primary Progressive Aphasia [19], is characterized by the striking and amodal loss of semantic knowledge involving the comprehension of words and related semantic processing in the context of a relative preservation of other cognitive functions [20]. These deficits in semantic processing reflect the progressive degeneration of the anterior temporal lobes [21]. In contrast, bvFTD involves the deterioration of social cognition, motivation, and decision-making and profoundly impacts interpersonal conduct [22–23]. These deficits are associated with atrophy primarily in the medial and orbital prefrontal cortices, spreading to lateral and medial temporal regions as the disease progresses [24, 25]. Behaviorally, both syndromes are associated with repetitive, compulsive, and rigid behaviors [26, 27] that may make it difficult to shift from one activity or thought to another. Converging evidence points to significant episodic memory dysfunction in bvFTD at a level comparable to that observed in AD [28, 29]. In contrast, recent episodic memory has been found to remain relatively preserved in SD, particularly when nonverbally loaded tasks are used [21, 30]. More recently, the capacity to imagine and anticipate possible future events has been shown to be significantly disrupted in both bvFTD [31] and SD [32, 33]. Despite such advances in our understanding of the nature and extent of episodic memory disruption in both syndromes, it remains unknown whether bvFTD and SD patients can remember to carry out actions at a future time point. Empirical examination of the integrity of PM in FTD syndromes represents an important line of inquiry, as findings from such an investigation would be invaluable to caregivers’ understanding of the ability of FTD patients to remember to carry out everyday future intentions (e.g., taking medication). The aim of this study was to examine PM performance and its associated cognitive mechanisms in SD and bvFTD patients and to compare their performance with matched AD patients. In this endeavor, we selected a naturalistic task to maximize generalizability to everyday forgetting. The frontal lobes are widely implicated in PM performance [2, 5] as well as the formation of future

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intentions [34, 35]. Given that the predominant locus of atrophy in bvFTD occurs within the frontal lobes, we hypothesized that bvFTD patients would demonstrate global impairments on the PM task. In contrast, the extent to which PM relies on semantic memory has not been explored, however, given the pivotal role of semantic processing in future oriented thought [32, 33, 48], we predicted that significant deficits in PM would be evident in the semantic dementia group. METHODS Participants A total of 24 dementia patients (bvFTD = 8; SD = 8; AD = 8) and 12 age- and education-matched healthy older controls were recruited through FRONTIER, the frontotemporal dementia research group at Neuroscience Research Australia, Sydney. All dementia patients met the relevant International Consensus Criteria for bvFTD [22], SD [19], and AD [36]. Briefly, clinical diagnoses were established by consensus among a multidisciplinary team comprising senior neurologist, occupational therapist, and neuropsychologist based on extensive clinical investigation, comprehensive neuropsychological assessment, and evidence of brain atrophy on structural neuroimaging. BvFTD patients presented with alterations in social functioning and interpersonal conduct, accompanied by a loss of insight, disinhibition, increased apathy, and emotional dysfunction. SD patients demonstrated a progressive loss of general conceptual knowledge, manifesting in significant naming and comprehension impairments, as well as prosopagnosia and/or associative agnosia, in the context of relatively preserved everyday episodic memory. Finally, the predominant complaint of AD patients related to significant episodic memory loss, in the context of preserved behavior and personality. All controls scored 0 on the Clinical Dementia Rating scale (CDR) [37], and 88 or above on the Addenbrooke’s Cognitive Examination-Revised (ACE-R) [38]. Exclusion criteria for all participants included prior history of mental illness, significant head injury, movement disorders, cerebrovascular disease, alcohol and other drug abuse, and limited English proficiency. Ethical approval for this study was obtained from the South Eastern Sydney and Illawarra Area Health Service and the University of New South Wales ethics committees. All participants, or their person responsible, provided

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informed consent in accordance with the Declaration of Helsinki. General cognitive screening Participants were assessed across the following neuropsychological tests. First, the ACE-R [38] was used as a measure of global cognitive functioning. The Rey Auditory Verbal Learning test (RAVLT) [39] was administered as an index of verbal episodic memory; the 3 minute delayed recall of the Rey Complex Figure (RCF) [40] for visuospatial episodic recall, and the Doors A subtest from the Doors and People test [41] as measure of non-verbal recognition. The Trail Making Test part A [42] assessed speed of information processing. To assess executive function, the difference in Time between the Trail Making Test part B and part A [42] was used as an index of mental flexibility. With the exception of the SD patients (due to associated semantic load of the tasks), the Hayling overall Scaled Score [43] was administered as an index of disinhibition. Verbal fluency (F,A,S) [44] was also assessed. Verbal semantic performance was measured using a measure of Naming and Comprehension from the Sydney Language Battery (SYDBAT) [45]. Lastly, to assess behavioral changes in the patient groups, caregiver ratings from the Cambridge Behavioural Inventory (CBI) [46] were obtained. Assessment of prospective memory A modified prospective memory task, previously used in acquired brain injury populations, was used [14]. This task was shortened to minimize floor effects associated with fatigue and increased cognitive demands in dementia patients. The shortened version takes 20 minutes to complete, and comprises three Time-based and three Event-based prospective memory items (described below). Participants were required to remember to complete these tasks while viewing and describing humorous cartoons as a filler task. A clock, a piece of paper, and a pencil were clearly visible for the duration of the task. The following instructions were given, “In this task you are going to do a number of things. I will read aloud some instructions and I want you to remember to do the action. You should use the pencil and paper to make notes to help you to remember the instructions. Also, you can use your watch or this clock, to help you keep track of the time.” Then, the following six instructions were read aloud by the experimenter, one after the other, followed by the filler task.

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Time-based prospective memory tasks 1. Remind the tester after 15 minutes not to forget her keys: “In 15 minutes time, I want you to remind me not to forget my keys.” 2. Requesting the tester for a pencil after 10 minutes: “In 10 minutes time, please ask me for a pencil.” 3. Opening or closing the booklet of filler task 5 minutes after the instruction was given: “In 5 minutes time please close the book you are working on.” Event-based prospective memory tasks 1. Putting a notebook under the table after an alarm rings (set to ring 13 min after the beginning of the session): “When the alarm rings, please put this notebook on the floor.” 2. Give the stopwatch back when the tester says that there are 10 min left: “When I tell you there are 10 minutes left, please give me this stopwatch.” 3. Give an envelope with “message” written on it to the tester at the end of session: “When I tell you we have finished the session, please give me this message.” All participants wrote the instructions down using the pen and paper provided in accordance with the experimenter’s instruction. Scoring of the prospective memory task Performance measures Each PM subscale (Time-based and Event-based) contained three items. For each item, one point was awarded for performing the correct action, and another point for completing it at the correct time (2 points × 3 items = 6 points per subscale). On the Time-based PM task, an action was considered correct if it was completed within five minutes of the instructed time. Anything that was completed outside this window was marked as incorrect. One further point was awarded if the participant used the external aid (notepad and pen) to take notes for any of the tasks in each subscale. This generated a possible total of seven points for each PM subscale and resulted in category-specific scores; Time-based score and Event-based score, each ranging from 0−7. The third performance outcome was the Total score, which was the sum of the Time-based score and Event-based scores, and ranged from 0−14, with higher scores denoting better PM performance. Statistical analyses Given the relatively small sample sizes under consideration, non-parametric statistical tests were used.

Kruskal-Wallis tests were conducted to investigate overall group effects, and subsequently, MannWhitney U tests were run to determine where group differences lay. Spearman rank correlations were run to explore potential relationships between performance on the prospective memory task and general neuropsychological test scores. Finally, Chi-squared tests, based on the frequencies of variables, were used to investigate group differences for categorical variables (e.g., gender). RESULTS Demographics The groups were well matched for gender and years in education (all p values >0.1). No overall group difference was found for age (p = 0.097). Lastly, no significant differences were evident between the patient groups for disease duration (months elapsed since onset of symptoms, all p values >0.2). Global cognitive functioning Neuropsychological test results are presented in Table 1. Briefly, overall group differences were found on the ACE-R screening measure (H(3)=26.480, p < 0.0001), with all patient groups scoring significantly lower than controls (SD, U = 0.000, p < 0.0001; bvFTD, U = 2.000, p < 0.0001; AD, U = 1.500, p < 0.0001). The SD group performed significantly poorer on the ACE-R than the bvFTD group (U = 1.500, p = 0.001), with the suggestion that the AD group were also more impaired relative to the bvFTD group (U = 13.500, p = 0.051). No other group differences were found for total ACE-R score (all p values >0.1). SD patients exhibited characteristic deficits in language as indicated by marked impairments in naming and comprehension (both U = 0.000, p = 0.001), and letter fluency (U = 11.500, p = 0.007), relative to controls. These language deficits occurred in the context of relatively preserved speed of information processing (Trail Making Test A, U = 27.500, p = 0.954), visual episodic memory (RCF 3 minute recall, U = 27.000, p = 0.160; Doors A, U = 11.500, p > 0.05), working memory (Digit Span, U = 13.500, p = 0.091), and mental flexibility (Trails B minus A, U = 22.000, p = 0.135). In contrast, the bvFTD group displayed pronounced executive dysfunction. Relative to controls, deficits in working memory (Digit Span, U = 9.000, p = 0.026), mental flexibility (Trails B minus A, U = 11.000,

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Table 1 Demographic and clinical characteristics of study samples (standard deviations in brackets).a,b Demographics and cognitive tests SD (n = 8) BvFTD (n = 8) AD (n = 8) Controls (n = 11) F test Post hoc test Gender (M:F) Age (y) Education (y) Disease duration (months) ACE-R (100) Trail Making Test A (s) RAVLT delayed recall (15) RCFT 3 min recall (36) Doors A (12) Digit Span Total (30) Trail Making Test B-A (s) Letter Fluency Hayling Total (Scaled Score) Naming (30) Comprehension (30) CBI Motivation (%) CBI Stereotypical (%) CBI Total (%)

7:1 64.8 (2.1) 14 (1.3) 60.4 (6.4) 58.3 (12.4) 39.1 (11.2) – 15 (5.9) 8.0 (2.7) 15.9 (4.9) 39.1 (11.2) 26.1 (12.4) – 5.3 (2.9) 15.8 (4.7) 48.8 (32.3) 54.7 (33.4) 35.5 (23.7)

6:2 64.1 (2.5) 11.6 (1.2) 61.1 (12.5) 83.5 (7) 46.4 (15.1) 3.1 (2.2) 5.9 (4.8) 8.5 (2.9) 14.9 (3.2) 106.4 (70.7) 24.3 (12.1) 2.6 (2.1) 22.9 (2.3) 27.9 (0.8) 82.5 (28.5) 58.6 (39.0) 43.5 (22.5)

6:2 62.9 (5.8) 12.8 (3.9) 55.6 (27.6) 68.5 (15.7) 93.6 (93.5) 4.2 (3.3) 5.8 (5.2) 7.8 (2.6) 12.1 (2.7) 121.5 (69.2) 27.6 (19.6) 3.7 (1.6) 19.8 (4.9) 25 (4.6) 20.6 (26.7) 11.2 (7.9) 19.9 (10.6)

6:2 70.0 (2.4) 13.9 (0.9) – 93.8 (3.3) 40.7 (13.5) 11.3 (2.3) 18.9 (5.8) 10.4 (1.8) 20.4 (4.7) 43.6 (18.4) 44.5 (11.2) 6.0 (0.8) 24.9 (2.0) 28 (2.5) – – –

ns ns ns ns *** ns ** *** ns * * * * *** *** ** * ns

ns AD < controls ns ns Patients < controls; SD < bvFTD ns bvFTD, AD < controls; bvFTD = AD AD, bvFTD < controls; SD = controls AD < controls AD, bvFTD < controls AD, bvFTD < controls SD, bvFTD, AD < controls bvFTD, AD < controls SD, AD < controls; SD < bvFTD, AD SD < controls, bvFTD, AD SD, AD < bvFTD AD < SD, bvFTD AD < bvFTD

a Maximum

score for each test in brackets where applicable. b Trail Making Test A available for 7 AD patients. RAVLT delayed recall available for 5 AD patients and 7 controls. RCFT 3 min recall available for 7 bvFTD and AD patients. Doors A available for 7 controls. Digit Span Total available for 7 controls. Trail Making Test B-A available for 7 SD and bvFTD patients and 6 AD patients. Hayling was available for 7 AD patients and 7 controls. * p < 0.05; **p < 0.005; ***p < 0.0001; ns, non-significant; ‘-‘, not applicable as task was not administered in this group.

p = 0.013), letter fluency (U = 10.000, p = 0.005), and response inhibition (Hayling, U = 6.000, p = 0.010) were observed. Impaired verbal and visuospatial episodic retrieval was also found (RAVLT 30 minute recall, U = 0.500, p = 0.001; RCF 3 minute recall, U = 3.500, p = 0.002) in the context of preserved visual recognition memory (Doors A, U = 15.500, p = 0.141), compared to controls. In contrast, semantic naming (U = 15.000, p = 0.128) and comprehension (U = 19.000, p = 0.285), as well as speed of information processing (Trail Making Test A, U = 20.500, p = 0.385), did not differ significantly between bvFTD patients and controls. AD patients exhibited characteristic domain-general episodic memory impairments relative to controls (RAVLT 30 minute recall, U = 0.500, p = 0.001; RCF 3 minute recall, U = 4.500, p = 0.002; Doors A Recognition, U = 10.000, p = 0.035). Additional impairments were observed on measures of working memory (Digit Span, U = 3.500, p = 0.004), mental flexibility (Trails B minus A, U = 9.000, p = 0.016), letter fluency (U = 17.500, p = 0.028), and response inhibition (Hayling, U = 5.500, p = 0.013), compared to controls. Further, AD patients demonstrated semantic naming deficits (U = 10.000, p = 0.033) in the context of intact comprehension (U = 15.000, p = 0.128) relative to controls. Lastly, speed of information processing in the AD group was not found to differ significantly from controls (Trail Making Test A, U = 13.500, p = 0.159).

Caregiver ratings of behavioral changes BvFTD caregivers endorsed more behavioral symptoms than those of the AD group (U = 8.500, p = 0.014), with no other group differences evident (all p values >0.2). Ratings of stereotypical behaviors were found to discriminate between patient groups (H(2) = 7.662, p = 0.020), with the SD and bvFTD patients rated as exhibiting more stereotypical behaviors than AD patients (SD, U = 6.000, p = 0.006; bvFTD, U = 13.000, p = 0.044), and no significant differences observed between SD and bvFTD patients (U = 30.000, p = 0.833). CBI motivation levels also differed between patient groups (H(2) = 11.179, p = 0.004), with bvFTD patients rated as less motivated than SD (U = 10.000, p = 0.020) and AD patients (U = 4.000, p = 0.003), and no difference between SD and AD patients (U = 16.500, p = 0.100). Prospective memory performance Overall prospective memory performance Overall PM performance is displayed in Fig. 1. Overall group differences were observed for total PM performance (H(3) = 18.564, p < 0.0001), with significant differences evident across both Time (H(3) = 18.329, p < 0.0001) and Event (H(3) = 15.021, p = 0.002) PM subscales. All patient groups scored significantly lower than controls for Overall PM performance (SD,

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Within-group comparisons, using Wilcoxon Signed Ranks tests, revealed equivalent Time and Event performance in bvFTD (p = 0.459), SD (p = 0.117), and control (p = 0.128) participants. AD patients, however, demonstrated significantly better Event relative to Time performance (p = 0.040). Relationship between prospective memory performance and neuropsychological variables

Fig. 1. Overall prospective memory (PM) performance by group. Error bars represent standard error of the mean.

U = 14.000, p = 0.012; bvFTD, U = 3.500, p < 0.0001; AD U = 0.500, p < 0.0001), with comparable overall PM performance observed between the patient groups (all p values >0.1) Performance on prospective memory subscales PM performance by subscale is displayed in Fig. 2. SD patients did not significantly differ from controls on Time-based performance (U = 23.500, p = 0.091), but showed impaired performance on the Event subscale (U = 11.000, p = 0.005). In contrast, both bvFTD and AD patients displayed significant deficits relative to controls on both the Time (bvFTD, U = 6.500, p = 0.001; AD, U = 1.000, p < 0.0001) and Event (bvFTD, U = 7.500, p = 0.001; AD: U = 7.000, p = 0.001) subscales. Direct comparisons between the patient groups revealed that SD patients scored significantly higher than AD patients for Time (U = 12.000, p = 0.038) performance. No other significant differences were evident between the patient groups for Time or Event performance (all p values >0.1).

Spearman R correlations, corrected for multiple comparisons at p < 0.01, were run to investigate relationships between PM performance and neuropsychological variables in the patient groups. For SD patients, overall PM performance was significantly associated with global cognitive functioning (ACE-R; r = 0.916, p = 0.001) and semantic naming proficiency (r = 0.822, p = 0.006). For AD patients, however, episodic memory integrity was implicated, as delayed recall on the RAVLT was found to correlate with overall PM performance (r = 1.000, p < 0.0001). Similarly, a trend for the same relationship between episodic memory recall and overall PM performance was evident in the bvFTD group (r = 0.790, p = 0.020). Correlations between Time and Event subscales and neuropsychological test measures are presented in Table 2. Only those relationships that reached significance at p < 0.01 are discussed. Most notably, for the SD group, Event-based PM deficits correlated strongly with semantic naming deficits (r = 0.899, p = 0.002), and difficulties with Time- and Event-based PM were also significantly related to poorer overall cognitive functioning (ACE-R; Time-r = 0.868, p = 0.005; Event-r = 0.831, p = 0.010). Episodic memory retrieval was differentially associated with the two PM subscales for the remaining

Fig. 2. Total prospective memory performance (PM) by group for (a) Time-based and (b) Event-based subscales. Error bars represent standard error of the mean.

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Table 2 Correlations between prospective memory and neuropsychological test performancea Patient group Time-Based SD bvFTD AD Event-Based SD bvFTD AD

ACE-R Total

RAVLT Delayed recall

RCFT 3 min recall

Naming

Trails B-A

Hayling overall scaled score

Letter fluency

– 0.944*** 0.671

0.218 0.182 0.418

0.706 0.098 0.146

−0.342 −0.091 0.000

– 0.390 −0.420

0.458 0.400 0.207

0.899** 0.220 0.478

0.090 −0.491 0.580

– −0.207 0.133

0.795 0.036 0.241

0.868** 0.621 0.290 0.831* −0.111 0.377

– 0.198 0.975**

0.721 −0.291 0.527

a RAVLT delayed recall available for 5 AD patients. RCFT 3 min recall available for 7 bvFTD and AD patients. Trail Making Test B-A available

for 7 SD and bvFTD patients and 6 AD patients. Hayling was available for 7 AD patients. *p < 0.01; **p < 0.005; ***p < 0.0001; ‘-‘, not applicable as task was not administered in this group. Table 3 Correlations between prospective memory performance and caregiver-rated behavioral disturbance on the Cambridge Behavioural Inventory Patient Group Time-Based SD bvFTD AD Event-Based SD bvFTD AD

Memory

Motivation

Stereotypical behavior

Everyday abilities

−0.819* −0.537 −0.311

−0.291 0.269 −0.507

−0.689 −0.872** −0.171

−0.787 −0.356 −0.313

−0.819* −0.248 −0.370

−0.642 −0.540 −0.302

−0.835* 0.188 −0.471

−0.787 0.476 0.118

*p < 0.01; **p < 0.005; ***p < 0.0001.

patient groups: for bvFTD patients, RAVLT 30 min delayed recall was associated with Time-based PM (r = 0.944, p < 0.0001), whereas for AD patients, RAVLT delayed recall was related to Event-based PM (r = 0.975, p = 0.005). Relationship between prospective memory performance and behavioral disturbance To investigate if PM performance related to behavioral changes experienced by patients in their everyday lives, we ran further Spearman rank correlations between PM performance and caregiver reports of behavioral change on the CBI. Significant inverse relationships denote that a decline in PM performance is associated with higher levels of behavioral disturbance. For SD patients, overall PM performance was inversely related to reported difficulties in memory (r = −0.819, p = 0.013) and everyday activities (r = −0.856, p = 0.007). In contrast, no association was evident between overall PM performance and behavioral disturbance in either the bvFTD or AD groups (all p values >0.1). Correlations between Time and Event subscales and behavioral disturbance are presented in Table 3. For SD patients, caregiver reported memory changes were inversely associated with Time (r = −0.819, p = 0.013)

and Event (r = −0.819, p = 0.013) subscales. Additionally, Event-based PM was found to correlate strongly with reports of stereotypical behaviors (r = −0.835, p = 0.010) in SD. For the bvFTD group, Time-based PM was strongly associated with reports of stereotypical behaviors (r = −0.872, p = 0.002). Of note, no significant associations between Time- or Event-based PM and behavioral disturbance were found in AD (all p values >0.2).

DISCUSSION This study is the first, to our knowledge, to investigate PM in FTD. Using a simple naturalistic task, we have demonstrated differential PM profiles among FTD syndromes and AD patients. While bvFTD patients exhibited global PM impairments, SD patients showed a relative preservation of Time-based PM. Correlation analyses revealed significant relationships between PM performance and specific cognitive functions, and point toward distinct underlying neurocognitive mechanisms underpinning PM deficits in each dementia syndrome. The most notable finding to emerge was the comparatively preserved capacity for Time-based PM in SD. This relative sparing of Time-based PM is supported by

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clinical and anecdotal reports that SD patients appear fixated on time [26]. The clinical observation of preserved orientation to time and simple calculation skills [21] as well as intact verbal and visual number processing and calculation [47] in SD are noteworthy in this context. It is possible that SD patients may be able to harness preserved numerical and time perception skills to successfully execute Time-based PM tasks. In contrast, marked impairments were evident for Eventbased PM in the SD group, and this deficit was strongly associated with difficulties in semantic naming. The finding of relatively spared Time-based PM in SD is intriguing given that this function is posited to be more cognitively demanding than Event-based PM due to increased reliance on self-initiated (endogenous) processes [3, 6]. Importantly, compromised Event-based PM in SD is in line with previous studies that have demonstrated striking deficits in future oriented thinking secondary to semantic loss [48]. Our results also reveal an important distinction between Event- and Time-based PM tasks, and in particular the sparing of a function that up until this point has not been investigated in SD patients. In contrast, bvFTD patients exhibited global PM deficits irrespective of subscale, scoring at the same level as AD patients. Importantly, difficulty with delayed episodic retrieval emerged as a common mechanism of PM dysfunction in bvFTD and AD. Our finding of an association between deficits in Timebased PM and impaired delayed memory recall in bvFTD may reflect the frontal contribution towards episodic memory processes. Given the widespread atrophy observed involving orbito-mesial frontal and antero-medial temporal regions [24, 25], and evidence of severe episodic memory deficits in bvFTD [28, 29], as well as more recent evidence documenting impairments in the ability to imagine upcoming events [31], it is not surprising that these patients are unable to remember to carry out future intentions. From a clinical perspective, the bvFTD patient thus presents with a constellation of difficulties that include a compromised capacity to remember the past, imagine the future, and remember to carry out actions in the very immediate future. Together, this converging evidence provides crucial information for the caregiver and clinician, particularly in regards to tailoring the immediate environment to the patient’s needs. Consistent with previous literature [12], AD patients exhibited global PM deficits irrespective of subscale. Additionally, we found these PM deficits in AD to be strongly associated with delayed episodic retrieval, which confirms earlier findings in clinical [49] and

pre-clinical [15, 50] AD. Our results indicate that the breakdown of episodic memory is exclusively associated with Event-based PM deficits in AD, which most likely reflect a failure to encode and retain the action to be implemented, rather than a breakdown in orienting to the external cue. In support of this argument, we found PM failure to occur even with the provision of external aids (i.e., writing the tasks down). As such, it is possible that AD patients fail to make an association between the event and the to-be-remembered action, converging with the finding that associative memory is impaired in AD [51, 52]. Our current findings have a number of important clinical implications. Firstly, the significant association between PM dysfunction and behavioral disturbance in FTD syndromes warrants attention. Caregivers of SD and bvFTD patients endorsed a similar magnitude of stereotypical behaviors, which were found to be significantly higher than those reported by caregivers of AD patients. In particular, we found caregiver reports of stereotypical behaviors to be associated with compromised Event-based PM in SD and Time-based PM in bvFTD. These results not only confirm clinical reports of repetitive or stereotypical behavior commonly observed in both FTD syndromes [26, 53], but also converge well with the position that these patients share difficulties with flexible thinking, thinking ahead in time, and shifting from the immediate perspective [54]. Perhaps most critically, our findings point to an association between stereotypical behaviors in FTD with impaired capacity for PM. On a practical level, future research is required to disentangle the precise direction of this relationship, and it will be imperative to determine if a breakdown in PM occurs due to the inability to interrupt inflexible routines or ongoing actions, or whether stereotypical behaviors, characteristic of FTD, contribute to impaired PM performance. One important but outstanding question is whether the PM deficits observed here translate to functional difficulties in FTD syndromes. Previously, PM deficits have been implicated in several key daily activities such as medication adherence and keeping appointments [55]. Further, caregivers of patients with AD have rated difficulties with PM to be more frustrating than retrospective memory failures [56]. Of particular functional concern is our demonstration of marked inability to remember to complete a simple task within the space of 10 to 15 minutes, despite the provision of external aids. These PM deficits are likely to have serious practical implications, for example if patients are left alone to cook food on the stove or in the oven. Therefore, our results may offer important

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insights for tailoring care to support individuals with PM deficits. Tailoring reminders to rely on Time-based processes may prove particularly useful in SD, whereas using spaced-retrieval based on implicit learning and behavior shaping, rather than simply repeating to be remembered information, may prove effective in AD [57]. A number of methodological limitations warrant consideration. First, it is important to note the relatively small group size in the current study. Although robust dissociations were achieved, replication in a larger study is necessary to confirm these findings. Additionally, the majority of our patient sample had not yet come to autopsy, and thus we did not have access to neuropathological data to definitively confirm the underlying disease pathology in each group. Replication of our results in patient cohorts with neuropathological data therefore represents an important area of future inquiry. Our findings reveal a number of important avenues for future study. While we have demonstrated a significant association between episodic memory impairments and PM deficits in bvFTD and AD, the precise contribution of retrospective versus prospective components of the PM task remains unclear. In the current study, the extent to which patients utilized the external aids (i.e., referring to the written instructions) was not recorded. It will be important to clarify how potential individual differences in encoding and strategy influence PM performance. Likewise, the use of the external clock to monitor checking of time represents an important avenue for understanding the specific strategies used by participants during the Time-based PM task. Such information may illuminate whether monitoring of time underpins successful Time-based PM in SD, particularly as greater clock monitoring has been found to result in better sustained performance on a Time-based PM task in healthy adults [5]. Such information would also add to clinical and anecdotal reports of fixation on time in SD patients [26] more generally. An additional area to consider is the semantic loading of the Event- and Time-based PM tasks. Given the association between semantic processing and Eventbased performance, future studies will be necessary to determine the nature of this relationship. Finally, from a theoretical standpoint, it will be important to explore the neural correlates associated with PM difficulties in SD and bvFTD with a view to determining the key brain structures essential for Time- and Event-based PM. In summary, this is the first study to investigate PM in FTD syndromes, and our findings point to differential disruption of PM processes in SD and bvFTD. The relative preservation of Time-based PM in SD

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is intriguing, and represents an important avenue for future research, with a view to tailoring specific functional interventions to improve the everyday life of the patient. ACKNOWLEDGMENTS We are grateful to the patients and their families for their support of our research. This work was supported in part by an Alzheimer’s Australia Dementia Research Foundation Grant, and the Australian Research Council Centre of Excellence in Cognition and its Disorders (CE110001021); COC is supported by an Alzheimer’s Australia Dementia Research Foundation PhD scholarship; MI is supported by an Australian Research Council Discovery Early Career Research Award (DE130100463). These sources had no role in the study design, collection, analyses and interpretation of data, writing of the manuscript, or in the decision to submit the paper for publication. Authors’ disclosures available online (http://www.jalz.com/disclosures/view.php?id=1895). REFERENCES [1] [2]

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