Examination of the metacognitive errors that contribute to anosognosia in Alzheimer's disease

Accepted Manuscript Examination of the metacognitive errors that contribute to anosognosia in Alzheimer’s disease Stephanie Cosentino, Ph.D., Carolyn Zhu, Ph.D., Elodie Bertrand, M.A., Janet Metcalfe, Ph.D., Sarah Janicki, M.D., Sarah Cines, B.A. PII:

S0010-9452(16)30224-6

DOI:

10.1016/j.cortex.2016.08.003

Reference:

CORTEX 1810

To appear in:

Cortex

Received Date: 29 December 2015 Revised Date:

27 July 2016

Accepted Date: 5 August 2016

Please cite this article as: Cosentino S, Zhu C, Bertrand E, Metcalfe J, Janicki S, Cines S, Examination of the metacognitive errors that contribute to anosognosia in Alzheimer’s disease, CORTEX (2016), doi: 10.1016/j.cortex.2016.08.003. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Examination of the metacognitive errors that contribute to

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anosognosia in Alzheimer’s disease

Stephanie Cosentino, Ph.D.1, 2, 3, Carolyn Zhu Ph.D.4, Elodie Bertrand, M.A. 2, 5,

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Janet Metcalfe, Ph.D.6, Sarah Janicki, M.D.2,3, and Sarah Cines, B.A.2

Cognitive Neuroscience Division of the Gertrude H. Sergievsky Center1,

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Taub Institute for Research on Alzheimer’s Disease and the Aging Brain2 and Department of Neurology3,

Columbia University Medical Center, NY, NY Department of Geriatrics and Palliative Medicine,

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Icahn School of Medicine at Mount Sinai4, NY, NY Pontificia Universidade Catolica5, Rio de Janeiro, Brazil

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Department of Psychology, Columbia University6, NY, NY

Corresponding Author:

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Stephanie Cosentino, Ph.D. CUMC 630 West 168th Street P&S Mailbox 16 NY NY 10032

212-342-0289 [email protected]

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ABSTRACT Disordered awareness of memory loss (i.e., anosognosia) is a frequent and clinically relevant symptom of Alzheimer’s disease (AD). The metacognitive errors which characterize

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anosognosia in AD, however, have not been fully articulated. The current study examined

metamemory performance as a function of clinically defined awareness groups using different task conditions to examine the extent to which specific metacognitive deficits (i.e., detecting,

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integrating, or being explicitly aware of errors) contribute to anosognosia in AD (n = 49). In the prospective condition of the metamemory task, analyses examining the association between

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awareness group, confidence (i.e., FOK) ratings, and memory performance demonstrated an interaction effect F (1, 43) = 5.16, p = .028 with only the aware group (n = 22) providing higher FOK ratings for correct responses compared to incorrect responses (p < .001). The unaware group (n=27) did not show this dissociation (p = .167), and also made higher FOK ratings for

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incorrect responses than the aware group (p = .048). There was no main effect of task condition on FOK, (F (2, 66) = 1.51, p = .228) with all participants providing comparable FOK ratings for memory performance whether ratings were made prospectively, retrospectively, or in the context

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of examiner feedback. The overall pattern of performance in the unaware group, whereby individuals did not sufficiently lower confidence ratings in the context of memory errors, and did

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not benefit from either retrospective assessment or examiner feedback, appears most consistent with a primary anosognosia in which memory failures are not available in explicit awareness.

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1. INTRODUCTION Disordered self-awareness in Alzheimer’s disease (AD) challenges patient safety, caregiver quality of life, and fundamental aspects of a patient’s independence related to decision

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making capacity (Cosentino, Metcalfe, Cary, De Leon, & Karlawish, 2011; Karlawish, Casarett, James, Xie, & Kim, 2005). Lack of self-awareness in AD, also referred to as anosognosia

(Babinski, 1914), has been described in reference to numerous abilities such as behavioral,

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emotional and memory functioning (Kotler-Cope & Camp, 1995; Vasterling, Seltzer, Foss, & Vanderbrook, 1995; Verhülsdonk, Quack, Höft, Lange-Asschenfeldt, & Supprian, 2013). In the

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current paper we use the term anosognosia to refer specifically to a clinically observed lack of awareness regarding memory loss. While several studies have investigated the cognitive correlates of anosognosia in AD, and metacognitive models have been applied to describe various mechanisms by which anosognosia may arise (Agnew & Morris, 1998; Ansell & Bucks,

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2006; Hannesdottir & Morris, 2007; Mograbi, Brown, & Morris, 2009; Mograbi & Morris, 2014), the nature of the metamemory disturbance in AD has yet to be fully characterized. Understanding the precise metacognitive errors that produce the clinical syndrome of

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anosognosia may ultimately assist healthcare professionals and family members with appropriate interventions when patients may not appreciate the presence, severity, or consequences of their

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cognitive deficits.

We previously developed an objective metamemory task that captures anosognosia in AD

(Cosentino, Metcalfe, Butterfield, & Stern, 2007; Cosentino, Metcalfe, Cary, et al., 2011). Specifically, the accuracy of an individual’s online predictions for memory performance on the metamemory task is lower in individuals with anosognosia than in those who are aware of their memory loss, independent of global cognition or memory performance. Moreover, there is

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evidence that this metamemory task measures a specifically self-referential process, unaccounted for by demographic variables or primary cognitive functions such as attention, executive functioning, or memory (Cosentino, Metcalfe, Holmes, Steffener, & Stern, 2011). As such, this

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tool is uniquely suited to investigate the metamemory errors which may give rise to the clinical symptom of anosognosia in AD.

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In the current paper, we examine the previously used, prospective version of the metamemory task as well as two new experimental conditions to tease apart specific

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metacognitive errors that may contribute to anosognosia in AD. These conditions were designed to evaluate the extent to which anosognosia reflects failure to either detect memory errors as they occur, integrate (i.e., accumulate and store) detected memory errors, or access knowledge of memory failures in explicit awareness. These three possibilities map broadly onto three forms of anosognosia as outlined by the Cognitive Awareness Model (CAM). In the first, a failure to

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detect and/or register errors as affectively salient at the level of a “comparator mechanism” is described as an executive anosognosia (Ansell & Bucks, 2006; Mograbi & Morris, 2014; R. Morris & Hannesdottir, 2004). This is differentiated from a mnemonic anosognosia, or the

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inability to integrate memory failures into a “personal database” in order to update one’s

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knowledge about his or her memory functioning. Finally, the CAM outlines a third form of impairment, primary anosognosia, reflecting direct compromise to the “metacognitive awareness system” which gathers information from both the comparator system and personal database, and makes it available in explicit awareness. In such a scenario, self-awareness is impaired when measured explicitly, but may still emerge through intact implicit systems as represented through behavioral or emotional reactions to memory failures (R. G. Morris & Mograbi, 2013).

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Given the pervasive memory deficits in AD, it is reasonable to conceptualize disordered awareness of memory loss in AD in terms of an amnestic deficit, or mnemonic anosognosia (Mograbi et al., 2009). Indeed, various pieces of evidence support the idea that patients with AD

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experience an outdated sense of self due to an inability to update their personal knowledge in the context of advancing memory loss (Mograbi et al., 2009). In line with this idea, some studies have shown that metamemory worsens as memory worsens in AD (Gallo, Cramer, Wong, &

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Bennett, 2012; Hannesdottir & Morris, 2007), although this is not always the case (Cosentino et al., 2007; Souchay, Isingrini, & Gil, 2002; Souchay, Isingrini, Pillon, & Gil, 2003) (Michon,

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Deweer, Pillon, Agid, & Dubois, 1994; Shaked et al., 2014). It has also been shown that individuals with AD improve their assessments of memory performance from pre-test to posttest, suggesting that while post-test estimations tap into immediate experience relatively accurately, such experiences do not get stored in long-term memory, resulting in pre-test

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estimations that rely on outdated perceptions of memory functioning (Ansell & Bucks, 2006). However, there are certain issues that complicate the conceptualization of disordered awareness in AD as a purely mnemonic based, or integration based, disruption. First, the fact

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that a subset of individuals with AD are acutely aware of their memory loss, despite the presence of severe episodic memory deficits, suggests that reduced awareness of memory loss necessitates

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a metacognitive deficit that extends beyond the inability to integrate or “remember” memory failures. Second, several studies have shown that patients with AD do not improve metamemory ratings when allowed to rate performance retrospectively (Banks & Weintraub, 2008; Rosen et al., 2014). Third, retrospective confidence ratings have been shown to be impaired in individuals with AD as compared to healthy controls (Dodson et al., 2011; Williamson et al., 2010), and have even been reported to be comparable to those in individuals with behavioral variant

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frontotemporal degeneration (bvFTD), a clinical population characterized by profound deficits in self-awareness (Rosen et al., 2014). A deficit in the retrospective assessment of memory functioning suggests that memory

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errors have either not been fully detected or, if detected, have not been processed explicitly

(Mograbi, Brown, Salas, & Morris, 2012). We previously reported that for incorrect recognition memory trials, individuals with anosognosia more frequently endorse a distractor item than

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individuals without anosognosia ,who are more likely to state that they don’t know the answer (Cosentino et al., 2007). This pattern of performance suggests that those with anosognosia either

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do not detect the memory failure, or fail to process it in conscious awareness, deficits that are consistent with executive and primary forms of anosognosia respectively, according to the CAM (Mograbi & Morris, 2014). Evidence from naturalistic action tasks argue in favor of an error detection problem, as patients with AD detect a relatively small percentage of errors in

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comparison to healthy controls, even when error detection is measured behaviorally and does not require explicit verbalization of the error (Bettcher, Giovannetti, Macmullen, & Libon, 2008; Giovannetti, Libon, & Hart, 2002). However, evidence from experimental cognitive studies

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suggest that individuals with AD who do not explicitly endorse awareness of memory loss show behavioral and emotional signs of such awareness, arguing in favor of a specific deficit in the

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explicit representation of awareness (Martyr et al., 2011; Mograbi et al., 2012). The current study prospectively examined the basis of metamemory errors as a function

of clinically impaired memory awareness (i.e., anosognosia) through the manipulation of task characteristics across several conditions of a previously validated metamemory test (Cosentino et al., 2007). To our knowledge, this is the first study to simultaneously and prospectively examine specific the contribution of specific metacognitive errors in an item by item fashion in

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individuals with AD, and to examine these issues in the context of anosognosia. In the previously described prospective condition of the episodic metamemory task, participants are asked to predict whether or not they will recognize the answers to each of 20 items (Yes, Maybe,

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or No). In addition, participants completed two new conditions of the task. In the retrospective condition, participants provided immediate post-dictions of their performance for each item to examine the extent to which metamemory is facilitated immediately following experience with a

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memory failure (i.e., the extent to which error detection is intact). Finally, in the feedback condition, individuals made predictions for performance but were provided with examiner

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feedback regarding their memory accuracy on an item by item basis. The pattern of performance across the three task conditions was expected to inform the extent to which particular deficits may underlie anosognosia.

Specifically, if anosognosia is primarily a function of impaired error integration (i.e.,

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mnemonic anosognosia), retrospective assessment should be better than prospective assessment (as errors are in immediate memory). Additionally, feedback wouldn’t significantly improve prospective assessment because individuals can presumably recognize a memory failure as it

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occurs, and correspondingly not need or be assisted by external feedback regarding the failure. Alternatively, if individuals primarily have an error detection problem (e.g., executive

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anosognosia), retrospective assessment should be comparable to prospective assessment. In addition, prospective assessments would be likely to improve with item by item feedback about memory failures. Finally, we consider the possibility that failure to improve in either the retrospective or feedback condition may represent a primary anosognosia, with an inability to become explicitly aware of memory failures. Results of this study have the potential to shed light

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on the specific deficits which give rise to anosognosia, and ultimately the strategies that may be applied to manage this condition. In line with previous results, we hypothesized that individuals with and without

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anosognosia would be comparable on demographic and cognitive variables, but that the

anosognosia group would demonstrate less accurate metamemory when ratings are made prospectively. Additionally, we hypothesized that the pattern of performance across

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metamemory task conditions would not be consistent with a mnemonic anosognosia (i.e.,

performance would not improve from the prospective to retrospective conditions). Rather, we

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expected the anosognosia group to demonstrate a pattern of performance consistent with either an executive or primary anosognosia. Either of these forms would be expected to result in comparable performance both prospectively and retrospectively, but could be differentiated to some extent based on the feedback condition, with improved performance suggestive of an

2. METHODS

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2.1 PARTICIPANTS

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executive anosognosia and a lack of improvement suggestive of a primary anosognosia.

49 individuals with mild to moderate Probable AD defined as a score of 18 or greater on

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the Mini-Mental State Examination (MMSE) (Folstein, Folstein, & McHugh, 1975) were recruited through the Columbia University Medical Center Department of Neurology Memory Disorders Clinic. Diagnoses were made according to the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association (NINDS-ADRDA) criteria. Individuals with a history of neurologic illness or injury, or ongoing psychiatric illness were excluded. All participants provided informed consent and were given monetary compensation (reimbursed $30.00 per visit).

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2.2 PROCEDURES Participants were seen three times for 2-hour test sessions, each approximately two weeks apart. This time frame was selected to limit the effects of cognitive and metacognitive testing on

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performance at subsequent test sessions while keeping the test sessions confined to the course of 1-2 months to reduce the risk of inter-test cognitive decline. The metamemory testing was a subset of a larger neuropsychological protocol. Participants were assigned a clinical rating of

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awareness at the start of the first test session, and then completed the prospective version of the metamemory test at the start of the first test session, prior to any cognitive testing. The

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prospective task condition was not counterbalanced with the other two conditions to enable examination of the extent to which the originally reported association between clinical ratings of awareness and prospectively rated metamemory were replicable (Cosentino et al., 2007). The retrospective and feedback conditions of the test were then counterbalanced across the second

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and third visits, and were administered at the start of the test session. A within subject design was applied such that all participants completed all conditions of the task. This study was

2.3 MEASURES

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approved by the Columbia University Medical Center Institutional Review Board.

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Clinically Rated Awareness (Anosognosia) Clinical ratings of memory awareness were assigned using a modified version of the Anosognosia Rating Scale (Reed, Jagust, & Coulter, 1993). Awareness categories were defined based on the response to the question, “Please tell me how you feel about your memory abilities”. Scores were assigned as follows: Full Awareness = Spontaneous complaint or ready admission of abnormal memory loss along with the recognition that the loss is consequential and atypical for age; loss is generally discussed in the context of disease; Moderate Awareness =

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Spontaneous admission of memory loss; however, loss is discussed in the context of normal age related changes; Shallow Awareness = Inconsistent or transient recognition of memory loss, or uncertainty regarding memory loss. Participants may acknowledge inconsequential memory

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loss; No Awareness = No memory problems reported. All responses were audio recorded and consensus scored. This scale has been shown in two separate studies to correlate with

metamemory performance in AD (Cosentino et al., 2007; Cosentino, Metcalfe, Cary, et al., 2011)

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and was used to group participants in the proposed study (Aware = Full to Moderate Awareness; Unaware = Shallow to No Awareness).

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Metamemory

The metamemory test was a modified episodic Feeling of Knowing (FOK) task. Specifically, after study and at the time of test, individuals were asked to make FOK judgments for each item on a three point scale including Yes, Maybe, and No. The metamemory task consisted of four

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trials with five items in each trial, yielding a total of 20 metamemory items. The stimuli consisted of five pieces of “pseudo trivia” regarding an individual and information about his or her background. Three versions of the task were administered as described below:

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Prospective Condition: The examiner read the following instructions, “During this task, I am going to tell you about five people. I will tell you their name and something about their

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background. Your task is to try to remember this information as best you can. Please listen carefully”. After the first learning trial was presented (e.g., Cole Porter attended law school in Chicago; Edward Jenner traveled to Asia to study philosophy, etc.), participants were asked to make prospective judgments for each item in response to written questions (e.g., Who attended law school in Chicago?). The examiner stated, “Please don’t answer aloud. There are eight possible answers on the next page. Will you know which one is right – Yes, Maybe, or No?”

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Once predictions were recorded, participants were provided with eight answer choices and asked to select the correct answer. The answer choices included the correct response, the correct answers for the remaining 4 stimuli (to control for basic familiarity effects), and 3 new

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distractors. In the prospective condition, the tester moved onto the next item. This process was repeated for learning trials 2 – 4 resulting in a total of 20 item-specific FOKs. Stimuli were presented in the same order across each of the four learning trials; questions and answer choices

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were presented in a pseudorandom order.

Retrospective Condition: This condition was identical to the prospective condition, with

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the additional component of a retrospective evaluation after every item, regardless of accuracy, in which the examiner asked the participant, “Do you think that was the correct answer – Yes, Maybe, or No?” Postdictions of “No” were automatically assigned if the participant chose not to select a response, or answered “I don’t know” during the recognition testing. The retrospective

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metamemory score derived from this condition examined the accuracy of postdictions of memory performance for all items.

Feedback Condition: This condition was identical to the prospective condition except

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that the examiner provided feedback regarding recognition memory performance after each item (e.g., “That is correct” or “That is incorrect”). There were no retrospective ratings included in

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this condition.

Metamemory Accuracy: The primary dependent variable examined for the metamemory

task was the relative accuracy of all item by item judgments (i.e., resolution) measured with the nonparametric Goodman-Kruskal gamma statistic, a rank order correlation, (Nelson, 1984). This correlation reflects the extent to which accuracy was high when predictions for performance were high, and accuracy was low when predictions were low, and was selected given its

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previously established association with clinical levels of awareness in several earlier studies (Cosentino et al., 2015; Cosentino et al., 2007). Gamma compares the relative number of concordant and discordant prediction/accuracy pairs, discarding “ties”, or instances in which

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either the rating or accuracy in one pair is equal to that in another pair. Limitations of gamma include a tendency to be pulled to an extreme value on the basis of only one concordance or discordance, and a possibility that no score can be calculated in the event of all ties. In order to

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address these limitations, gamma scores were corrected in line with previous suggestions

(Souchay, Moulin, Clarys, Taconnat, & Isingrini, 2007). This correction has been applied in the

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context of signal detection theory to address instances in which hit rates are equal to one or false alarm rates are equal to zero, resulting in undefined signal detection measures (Snodgrass & Corwin, 1988). When applied to the calculation of gamma, this correction entails adding 1 to the overall number of concordances as well as the overall number of discordances. This adjustment

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draws scores slightly away from extreme values and assigns a score of zero when a score would otherwise be undefined in the case of all ties. For example, if an individual made judgments of “Yes” for every item, regardless of performance, each item would be tied with every other item

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and a score would thus be incalculable. By adjusting the calculation, this person’s performance is considered equal to 0, representing a random association between predictions and

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performance. The correlation between calculable gamma scores and the adjusted scores in this sample was 0.96 (p < .001). In addition to an adjusted gamma score, the Hamman coefficient was calculated as an alternative method of examining metamemory accuracy that is less sensitive to ties in the data (Schraw, 2009).

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Memory Memory was measured using the Philadelphia Repeatable Verbal Learning Test (PVLT) (Price et al., 2009). The PVLT, used to measure memory, is a list-learning task in which participants are

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required to learn 9 words (comprising three different categories: fruit, tools, and furniture) over the course of five trials for a total possible immediate recall score of 45. The primary dependent variable was delayed recall after approximately 30 minutes.

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Executive Functioning

Executive functioning was measured using a phonemic fluency test (Stuss & Benson, 1986).

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Participants were given three 60-second trials to generate words beginning with the letters “F, A, and S.” Total score represented the number of words generated excluding proper nouns and grammatical variations of the same word (i.e., eat, eating). The primary dependent variable was

2.4 DATA ANALYSIS

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the average total score across the three letters.

To examine the extent to which anosognosia was associated with reduced relative

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accuracy of metamemory ratings in the prospective condition as previously reported (Cosentino et al., 2007; Cosentino, Metcalfe, Cary, et al., 2011), univariate ANOVAs were used to examine

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differences in metamemory (i.e., gamma, Hamann) as a function of anosognosia. If metamemory was indeed different across aware and unaware individuals in the prospective condition as hypothesized, a 2 X 3 repeated measures ANOVA would be used to examine differences in metamemory across task conditions (prospective/retrospective/feedback) as a function of awareness group (aware/unaware), with particular interest in examining patterns of performance in the unaware group. However, as metamemory was not different across aware and

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unaware individuals in the prospective condition, analyses were conducted to examine the two components of the metamemory score (i.e., FOK rating and memory accuracy) more closely. Specifically, a 2 X 2 ANOVA was applied to examine the level of confidence (i.e., FOK ratings)

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in the prospective condition as a function of memory accuracy (correct/incorrect; within-subject factor) and group (aware / unaware; between-subject factor). (Conducting this comparison in the prospective condition only enabled the greatest statistical power as the highest number of

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participants completed this condition). Finally, a 3 x 2 x 2 mixed-model ANOVA, with task condition and memory accuracy as within-subject factors, and group as a between-subject factor,

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was used to examine FOK ratings as a function of memory accuracy and group, as well as task condition. RESULTS 3.1 Descriptive Data

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49 individuals completed the prospective condition of the task, 42 completed the retrospective condition, and 39 completed the feedback condition. 22 participants were clinically rated to have no anosognosia (i.e., aware group) and 27 participants were clinically judged to

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have anosognosia (i.e., unaware group). See Table 1 for demographic information and cognitive scores as a function of awareness group. ANOVAs were used to examine the hypotheses that the

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groups would be comparable on demographic and cognitive variables, but that the unaware group would demonstrate lower relative accuracy for prospective metamemory as measured by gamma and Hamann. As expected, ANOVAs revealed no differences in demographic or cognitive variables across the awareness groups. However, there was also no effect of group on gamma scores, F(1, 47) = 1.91, p = .17 or on Hamann scores, F(1, 47) = 2.39, p = .13 in the prospective condition. Given the lack of a main effect of awareness on metamemory as measured

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with relative accuracy scores in the prospective condition, a repeated measures analysis examining changes in relative accuracy as a function of task condition was not conducted. Table1. Cognitive, Demographic, and Metamemory Variables by Clinical Awareness Group

3.2 FOK (confidence) ratings

p .67 .79 .22 .37 .26 .91 .40 .17 .13

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F / χ2 .19 .07 1.57 .81 1.27 .01 .51 1.91 2.39

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MMSE Memory Executive Functioning Age Education Female Caucasian Gamma Hamann

Unaware 23.85 (2.74) 23.61 (4.92) 11.55 (4.49) 78.87 (9.11) 15.33 (3.35) 67% 93% 0.15 (0.55) 0.49 (0.43)

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Aware 24.18 (2.54) 23.45 (6.15) 13.19 (3.69) 76.40 (10.09) 16.36 (2.92) 68% 86% 0.36 (0.52) 0.65 (0.29)

As metamemory was comparable across aware and unaware individuals in the prospective condition, we examined the component parts of the metamemory score (i.e., FOK

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ratings and memory accuracy) more closely. FOK (i.e., confidence) ratings of Yes, Maybe, and No were translated into ordinal ratings of 1, 0.5., and 0, respectively for statistical analyses. FOK was examined as a function of memory accuracy (correct/incorrect) and group

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(aware/unaware) in the prospective condition using a 2 x 2 mixed-model ANOVA. Results showed a main effect of memory accuracy (F (1, 43) = 17.57, p < .001), with higher FOK ratings

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for correct versus incorrect responses. There was no main effect of awareness group (F (1, 43) = .42, p = .520). However, there was a significant interaction effect between accuracy and awareness group, F (1, 43) = 5.16, p = .028. Pairwise comparisons showed that the aware group made lower (i.e., less confident) FOK ratings for incorrect responses as opposed to correct responses (p < .001), but the unaware group did not (p = .167). In addition, the unaware group made higher FOK ratings for incorrect responses than did the aware group (p = .048). There was no difference in FOK ratings between groups for correct responses (p = .726).

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A three-way ANOVA was then performed to examine the extent to which the association between awareness, FOK ratings, and memory accuracy varied across task condition (i.e., prospective, retrospective, feedback). Table 2 presents average FOK ratings as a function of

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group, task condition, and memory accuracy. Again, a main effect of accuracy was observed, suggesting that, overall, the FOK ratings varied depending on memory accuracy F (1, 33) = 32.49, p < .001. There was no main effect of group or task condition (F (2, 66) = 1.51, p = .228),

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and in this model there were no interaction effects (accuracy x group (F (1,33) = 1.06, p = .311), condition x accuracy (F (2, 66) = 0.24, p = .790), condition x group (F (2, 66) = 0.77, p = .469),

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or condition x accuracy x group (F (2, 66) = 0.88, p = .422)).

Table 2. Average FOK Ratings by Group, Condition, and Memory Accuracy Unaware

Aware

Correct

Incorrect

Correct

Prospective

0.19 (.17)

0.38 (.28)

0.31 (.19)

0.36 (.24)

Retrospective

0.27 (.22)

0.43 (.32)

0.35 (.23)

0.45 (.32)

Feedback

0.29 (.23)

0.43 (.27)

0.31 (.25)

0.44 (.28)

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Incorrect

Note. FOK ratings include values of 0, .5, and 1 corresponding to ratings of No, Maybe, and Yes.

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Table 3. Average Frequency of Predictions for Incorrect Answers Rating

Aware

Unaware

Yes Maybe No

.07 (.12) .26 (.30) .67 (.30)

.09 (.14) .44 (.24) .47 (.28)

Retrospective

Yes Maybe No

.12 (.20) .31 (.24) .57 (.29)

.12 (.20) .46 (.31) .42 (.35)

Feedback

Yes Maybe No

.11 (.23) .36 (.32) .53 (.32)

.11 (.24) .39 (.30) .50 (.33)

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Prospective

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4. DISCUSSION The aim of the current study was to identify the type of metamemory errors that give rise to the clinical symptom of anosognosia in AD. Using three conditions of an episodic feeling of

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knowing (FOK) task, we examined the extent to which deficits in the ability to detect, integrate, or be explicitly (consciously) aware of memory failures may contribute to anosognosia. Existing models of anosognosia in AD posit several mechanisms by which memory awareness may be

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impaired in AD (Mograbi et al., 2009; Mograbi & Morris, 2014; R. Morris & Hannesdottir, 2004). Previous studies have lent indirect evidence to the idea that anosognosia may reflect a

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mnemonic deficit driven by an inability to integrate memory failures over time (Ansell & Bucks, 2006; Moulin, 2002; Moulin, Perfect, & Jones, 2000), an executive syndrome stemming from an inability to detect memory errors as they occur (Banks & Weintraub, 2008; Cosentino et al., 2007; Negro & Alberti, 2011; Rosen et al., 2014), or a primary anosognosia in which errors may

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be detected but not processed explicitly (Martyr et al., 2011; Mograbi et al., 2012). Results of the current study appear to be most consistent with the idea that impairment in the explicit awareness of memory failures may contribute to anosognosia in AD.

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As our primary approach to examining metamemory across task conditions, we calculated gamma scores as a prospective measure of memory monitoring. Gamma reflects the

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degree to which individuals adjust predictions in accord with variations in actual performance and has been shown to map onto clinical levels of awareness (i.e., anosognosia) in AD (Cosentino et al., 2015; Cosentino et al., 2007; Cosentino, Metcalfe, Cary, et al., 2011). The pattern of gamma scores across the aware (M = 0.36) and unaware (M = 0.15) groups in the current study was in the expected direction; however, contrary to expectations, there was significant variability within each group and correspondingly no statistical between-group

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difference in scores. The same was true when using the Hamann coefficient as a measure of memory monitoring. This variability could reflect a number of issues including: 1) imprecise clinical groupings resulting from the subjectivity of the anosognosia rating scale; 2) limitations

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of the memory monitoring scores, and/or 3) differences in the types of awareness captured by online versus more global measures of memory awareness. Of note, while the unaware group achieved gamma scores that are comparable to what has previously been reported (-0.02 through

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0.28), the aware group achieved relatively low scores as compared with previous reports (0.47 through 0.76) suggesting that the group of participants in the current study had a more difficult

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time than expected with the task for reasons that are unclear. Future work is needed to examine more precisely the conditions under which gamma or other online metamemory scores are consistent or inconsistent with clinical levels of memory awareness measured offline, at a more global level.

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In the absence of an association between overall memory monitoring scores and anosognosia, we conducted follow up analyses to more closely examine potential memory monitoring differences in relation to clinically rated memory awareness. Specifically, we broke

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down the overall metamemory scores into their component parts (i.e. confidence ratings and memory accuracy) to examine how each awareness group rated their confidence in their memory

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performance as a function of their memory accuracy, first in the prospective condition only. Results demonstrated that only the aware participants supplied lower confidence ratings for incorrect as opposed to correct answers. Table 2 illustrates this decrease in confidence levels in the prospective condition as a function of memory accuracy most notably in the aware group. Moreover, the unaware (i.e., anosognosia) group had greater levels of confidence in incorrect answers than the aware group. Qualitative examination of specific confidence ratings in the

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prospective condition, presented in Table 3, suggests that this difference in confidence was not dramatic, but may have reflected a subtle tendency to predict “Maybe” rather than “No” for incorrect responses. Interestingly, the unaware group did not have lower confidence for correct

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responses than the aware group, pointing to some degree of overconfidence in this group (rather than a non-specific disruption in metamemory).

Given the relatively overconfident ratings in the anosognosia group for incorrect items in

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the prospective condition of the task, we were interested in determining whether the association between confidence ratings and memory performance was strengthened in this group under

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different task manipulations. Results demonstrated that there was no effect of task condition on FOK ratings. That is, the unaware group did not provide different FOK ratings in either the retrospective or feedback conditions. The failure to make more accurate FOK ratings in the retrospective condition, when individuals are given the opportunity to evaluate performance

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immediately following experience with memory failures, argues against a mnemonic anosognosia, as does the fact that episodic memory was comparable across awareness groups in the current study. Rather, the comparability of FOK ratings across the prospective and

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retrospective conditions could reflect either deficient error detection, or impairment at the level of explicit awareness, and is consistent with various previous studies demonstrating that

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individuals with AD do not provide more accurate post-task ratings than pre-task ratings, and perform more poorly than controls on retrospective measures of metamemory (Banks & Weintraub, 2008; Rosen et al., 2014; Williamson et al., 2010). Seemingly at odds with these findings are results from at least two studies that have

suggested that patients with AD are able to improve their estimations of performance after being exposed to a task (Ansell & Bucks, 2006; Moulin et al., 2000). However, in both studies, the

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critical improvement in estimations of memory recall was from pre-study to post-study of the task material. That it, they were exposed to the demands of the task but did not perform the task. Thus, there is evidence that patients with AD are able to reduce their expectations for recall

estimations of post-test performance would be accurate.

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performance based on exposure to the task demands. Yet it is not clear whether in such cases, Data from Ansell and Bucks (2006)

partially speak to this issue as their study included repeated memory and metamemory testing.

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Specifically, participants completed pre and post-study ratings for recall of a memory list, and repeated this procedure twice with additional word lists. Thus the pre-study estimations for the

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second and third memory tests can, in a sense, be considered post-task estimations since participants already completed the memory task at least once. The authors found that in each subsequent presentation of a memory list, participants reduced pre-study expectations for performance as compared to previous trials, suggesting that performance with the previous

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memory task helped to form more accurate future expectations for memory performance. Nonetheless, participants continued to overestimate memory performance throughout all three memory tests as compared with healthy controls. As such, previous findings and current results

an explicit level.

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do not preclude a deficit in error detection or compromised awareness of memory performance at

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In the presence of an error detection deficit, it is possible that metamemory may improve

with externally provided feedback regarding individual memory failures. There is evidence that patients with AD are better able to incorporate external feedback regarding performance into predictions for future recall performance than are patients with bvFTD, and are comparable to healthy controls in such ratings (Rosen et al., 2014). However, in that study, global estimations for recall performance in the AD group were relatively intact prior to task performance,

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suggesting that the accuracy in the post-feedback condition was not necessarily specific to the presence of feedback. Moreover, participants were provided with global feedback and immediately asked for a prediction (e.g., “You correctly remembered 10 of the 20 word pairs. If

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I gave you a similar list of 20 word pairs to remember, how many do you think you would

remember?”). Whether or not item by item feedback can effectively improve the accuracy of metamemory estimations in AD remains to be determined.

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In the current study, external feedback did not influence FOK ratings in the unaware group. That is, despite being told the outcome of their recognition memory performance on each

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individual item, the unaware group did not shift their confidence ratings regarding their performance on the remaining trials in that condition. The ineffectiveness of external feedback argues against an executive anosognosia in which an error detection problem should in theory be improved when errors are detected through feedback. Moreover, while it is not a necessarily a

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defining feature of the CAM that an executive anosognosia would correlate with “executive functioning” as measured with cognitive testing, the original description of the executive anosognosia subtype associates this form of anosognosia with frontal or dysexecutive syndromes

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(Agnew & Morris, 1998). It is therefore worth noting that executive functioning as measured in the current study with a phonemic fluency task was not associated with awareness in this sample

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of AD patients.

The fact that FOK ratings were comparable across all three conditions is most

parsimoniously explained by the concept of a primary anosognosia. In this conceptualization, neither retrospective assessment nor feedback would enhance awareness because the deficit is not at the level of either detection or integration. Indeed, in the CAM, primary anosognosia is defined as a deficit in explicit awareness of memory failures despite the fact that errors are both

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detected and integrated; and anosognosia reflects the inability to synthesize information from the personal database and comparator mechanism into an emergent explicit awareness. Recent work supports the dissociation between implicit and explicit awareness of performance in individuals

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with AD. Specifically, there is evidence that individuals who fail to explicitly endorse memory problems or to even explicitly acknowledge errors as they occur, show behavioral signs (i.e., facial expression) indicating that they detect individual memory failures (Mograbi et al., 2012),

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and increased time to read dementia related words on an emotional stroop task (Martyr et al., 2011).

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It should, however, be acknowledged that another possibility presented by the revised CAM is that a disruption in processing the emotional salience of errors might occur in an executive anosognosia, an abnormality that could prevent an individual from fully processing and benefiting from feedback (R. G. Morris & Mograbi, 2013). The ability to benefit from

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feedback requires the individual to register the information about each individual error as important, and to apply this information to generate realistic expectations for future performance. It has been proposed that in the case of an executive anosognosia, impaired error detection may

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reflect affective blunting such that errors are deprived of their emotional salience (Mograbi & Morris, 2014). Thus even though the errors have been “detected” for the individual, errors may

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be ignored or normalized, and therefore may not influence an individual’s expectations for future performance. In this scenario, it is possible that individuals would not improve their performance in the feedback condition due to a lack of emotional motivation or appreciation for the emotional salience of errors. Further studies should directly compare the extent to which anosognosia in AD is characterized by errors losing their affective salience versus errors failing to emerge into explicit awareness.

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Recent investigations of the neuroanatomic correlates of metamemory in AD have provided interesting information and new perspectives with which to consider the substrates of disordered memory awareness. Structural and functional imaging studies exploring the neural

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correlates of unawareness in individuals with AD have highlighted associations with numerous regions including inferior, medial and orbital frontal cortices, temporal and parietal regions, and midline structures such as the cingulate cortex (Amanzio et al., 2011; Shany-Ur et al., 2014; for a

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review, see Zamboni & Wilcock, 2011). Based on the findings from the current study, we

speculate that compromise to brain networks critical for translating information about memory

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failures into conscious awareness may play a role in producing the clinical symptom of anosognosia in AD. This idea is supported by a recent structural imaging study which revealed an association between metamemory and the integrity of the right insula in a group of older adults with and without AD (Cosentino et al., 2015). A number of studies have illustrated a role

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for the right insula in supporting multiple aspects of self-awareness, seemingly through its role in supporting performance monitoring (Klein et al., 2007), (Ullsperger, Harsay, Wessel, & Ridderinkhof) and in particular, the conscious perception of errors (Hester, Foxe, Molholm,

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Shpaner, & Garavan, 2005). In that paper, we conceptualized the right insula’s role in metamemory as supporting the conscious detection of errors, and suggested that impaired

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metamemory in AD might therefore be most consistent with either a primary or executive anosognosia. The current behavioral results tip the scale toward the idea that impairment exists in the conscious perception of errors, more so than the detection of errors, and that a primary anosognosia may best fit the profile of anosognosia in AD.

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Limitations To our knowledge, this was the first study to prospectively and simultaneously evaluate the extent to which specific metacognitive deficits may contribute to anosognosia in AD. A

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strength of this study was the availability of both clinical awareness data as well as repeated metamemory assessments within participants. However, there were several limitations, the first of which was an incomplete counterbalancing procedure. While the retrospective and feedback

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conditions of the task were counterbalanced across the second and third visits, the prospective condition of the task was always administered at the first visit. This procedure was adopted to

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enable examination of clinical ratings of awareness in relation to metamemory (in the prospective condition without exposure to other conditions of the task). A potential drawback of this procedure is that any improvements in metamemory after the first visit could be interpreted as reflecting previous exposure to metamemory testing. Given the fact that performance on the

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retrospective and feedback conditions did not represent statistically significant improvements, however, practice effects are not a concern. A second limitation is that the task conditions were not designed to evaluate the extent to which errors are deprived of their affective signature.

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Future work should compare head to head the extent to which anosognosia in AD can be linked to deficient processing of the emotional salience of memory failures versus impairment in the

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explicit awareness of memory failures. Summary and Conclusions The current study examined patterns of metamemory performance under different

conditions across clinically defined anosognosia groups. Individuals with anosognosia did not provide dissociable confidence ratings for correct versus incorrect answers, and provided higher confidence ratings for incorrect items than those rated to be aware. Participants with

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anosognosia did not change their confidence ratings when allowed to rate performance retrospectively, or when provided with external feedback about memory performance, implicating an inability to process information about memory failures at an explicit level. It is

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certainly possible that memory awareness deteriorates under different circumstances across

individuals, such that disordered awareness reflects a heterogeneous set of metacognitive deficits rather than a singular condition. Future studies with the resources to conduct rigorous cognitive

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testing in a large sample of clinically characterized individuals have the potential to address the

STATEMENT OF FUNDING

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presence of heterogeneous etiologies of anosognosia across individuals.

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This work was supported by a Paul B. Beeson Career Development in Aging Award (1 K23 AG032899) funded jointly by the National Institute on Aging and the American Federation of Aging Research. Elodie Bertrand acknowledges financial support from the Capes Foundation, Ministry of Education of Brazil (Grant BEX 3489/15-9).

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