Heterogeneity of Cognitive Anosognosia and its Variation with the Severity of Dementia in Patients with Alzheimer’s Disease

Abstract

Currently, the lack of awareness of deficits, i.e., anosognosia, is a major obstacle in the healthcare circuit that delays the diagnosis of Alzheimer’s disease (AD). However, a clear framework is lacking in the literature related to this phenomenon in terms of its definition, mechanisms, and objects. The aim of this study is to assess the different levels of cognitive anosognosia using a prediction-performance procedure and to identify the potential correlates of these levels. A sample of patients with probable AD was divided into three groups according to the severity of dementia (mild (MiD), moderate (MoD), and moderately severe (MSD) dementia), ranked according to the results of the Mini-Mental State Examination. We observed the following three scores: the real score, the prediction score, and the anosognosia score. These scores were calculated based on the prediction-performance task MISAwareness from the Dementia Rating Scale for cognitive processes (i.e., Attention, Initiation, Conceptualization, Construction, and Memory). We obtained a strong plateau effect between the MiD and MoD groups for anosognosia scores for actual performance or prediction for both the level of overall functioning and for specific processes. The sole exception was the result for memory processes. Moreover, the profiles of the patients’ responses on the Memory subscale were substantially different and, indeed, opposite from those for the other processes. The main results confirm the multidimensionality of anosognosia and its variability with the stage of dementia and specifically implicate memory processes that indicate a cleavage between memory and other cognitive functions.

Keywords

Alzheimer’s disease anosognosia awareness cognition dementia executive functions memory self-assessment

INTRODUCTION

Anosognosia in dementia refers to an impaired ability to recognize the presence or appreciate the severity of deficits in sensory, perceptual, motor, affective, or cognitive functioning [1]. There is a consensus that this phenomenon should be considered to be an important symptom of Alzheimer’s disease (AD) [2 –4] and one of the key factors that delays diagnosis [5].

In the context of AD, anosognosia has been shown to be a frequent feature, and the worsening of this symptom could be related to the progression of the pathology [6]. Notably, the prevalence of anosognosia varies widely between 20% and 81% according to previous studies [7, 8].

Numerous studies have highlighted the positive correlations between anosognosia and the severity of dementia [6 , 9–16], but some have reported conflicting results [8 , 18]. In the same way, negative correlations have been found between anosognosia and global cognitive function based on the Mini-Mental State Examination (MMSE) [3 , 19], but some authors have not observed this link [20].

Indeed, it is difficult to generalize the results. Many anosognosia studies have produced contradictory results, partially due to different methodologies [21]. The tools and measures of anosognosia differ between studies and include the judgment of a relative [7], the clinical judgment of professionals [22], and comparisons between self-reports and actual performance [23 –26]. The latter method reflects the cognitive formulation of anosognosia, but the non-ecological nature of the task can disrupt predictions. The MISA performance prediction procedure (for Multidimensional Isomorphic Simple Awareness) was developed as a result of a review of these methods [27] to overcome the current limitations of measures of anosognosia.

Additionally, anosognosia for memory has been widely explored in recent years, and these explorations have highlighted some important facts [28, 29]. Specifically, the overestimation of performance appears to be greater when tasks include memory processes [4 , 31]. Moreover, research has shown that measures of memory monitoring are cues to the components operating in anosognosia [32, 33]. Few studies have investigated other cognitive processes or functions. In particular, executive functions are shown to be inversely correlated with the Anosognosia Questionnaire for Dementia. A deficit of executive functions seems to impact the process of decision-making, which is known for its potential involvement in the mechanisms of anosognosia [34]. Executive functions seem partially responsible for the anosognosia of behavioral disturbances [35]. Some studies have shown a link between anosognosia and several mood disorders, including depressed mood, anxiety, and apathy [36, 37]. Moreover, the presence of neuropsychiatric symptoms is one of the predictors of the anosognosia score [37]. Finally, poorer functional abilities also predict the presence of anosognosia [37]. Activities of daily living, much more than memory or socio-emotional functioning, are impacted by anosognosia [38]. However, some authors have shown different influences from anosognosia on these domains [3 , 39], and the effects of these influences differ [40]. Furthermore, Antoine et al. [27] showed that awareness of memory disorders is distinct from the awareness of other cognitive deficits. Specifically, awareness of memory disorders is only weakly correlated with awareness of other deficits, and it is the only such deficit that is not significantly correlated with global cognitive efficiency. This result supports the supposition of the separate dimensions of cognitive anosognosia. Many studies have also shown that correlations between anosognosia and cognitive impairments exist [3 , 19], but others have failed to identify such correlations [20].

These results explain a substantial portion of the variability and, thus, the heterogeneity of the phenomenon of anosognosia [13 , 41–43], particularly in the cognitive domain.

In the present study, we attempted to define different levels of anosognosia in all cognitive processes to complement those for memory that are currently addressed in the literature. This goal required reliance on a tool that accounts for the limitations of conventional measures of anosognosia, i.e., the MISAwareness performance prediction procedure [27]. Therefore, we focused on potential correlates of this variation using overall neuropsychological functioning and specific cognitive processes.

We also sought to clarify the bonds between the severity of dementia and the level of anosognosia across three stages of dementia in terms of the anosognosia profiles of cognitive processes.

METHOD

Participants

This observational and prospective study included a sample of 97 patients who had diagnoses of probable AD according to the National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer’s Disease and Related Disorders Associations (NINCDS-ADRDA) criteria [44] and had MMSE [45] scores between 10 and 26.

Several different centers located in urban and rural areas of the north of France were contacted. The centers included those serving relatively autonomous elderly individuals (i.e., daytime centers, elderly residencies, and retirement homes) and centers for dependent persons (i.e., medical-care homes).

Consent was obtained from all of the participants prior to the testing sessions in accordance with the Declaration of Helsinki.

MATERIALS AND PROCEDURE

First, several sociodemographic and medical variables were collected from the patients’ medical records. Second, cognitive evaluations were performed for each patient in single sessions.

Cognitive assessment

Overall cognitive functioning was assessed using the MMSE and the Dementia Rating Scale (DRS) [46].

The MMSE is the most commonly used tool for screening for cognitive impairments in dementia, and its scores range from 0 to 30 (higher scores indicate less cognitive deterioration).

The DRS is a self-assessment scale with 36 items, and is sensitive at the lower ends of functioning and differentiates the level of deficits.

Anosognosia assessment

The Multidimensional Isomorphic Simple Awareness (MISA) procedure was used to assess anosognosia among the patient groups [27]. This tool is based on subjective self-ratings that are compared with actual objective neuropsychological test performance. The patients were asked to predict their DRS performance on a dichotomous scale for each of the tasks of the DRS after hearing and seeing the task and prior to actually performing the task.

In the DRS instructions, items are arranged hierarchically, so that more difficult items are presented first. If a patient performs adequately on the initial items within a given subscale, full credit is given for the remaining items in that same subscale. Consequently, the prediction tasks are concerned only with the first items of each subscale. Each of those DRS difficult items and associated material were presented one by one by the researcher. Thus, the real scores (RS) corresponded to the number of good answers at these items and pointed the level of deficit of the actual performance. A prediction score (PS) was calculated for each subscale and the overall DRS. There are four possible cases: When a participant predicted a correct performance, but he did not perform adequately on the item, the PS was set as the lower correct performance and full credit is given for the remaining items in that same subscale. When a participant predicted a correct performance and he performed adequately, the PS was set at the real performance level (RS) and full credit is given for the remaining items. When a participant predicted a wrong performance, but he performed adequately on the item, the PS was set at the real performance level (RS) and full credit is given for the remaining items. When a participant predicted a wrong answer and he did not perform adequately on the item, the PS was set at the real performance level (RS) for this item as for the remaining items in that same subscale. This method enables to focus on the sub-assessments since the difference between the actual performance (RS) and the predicted score (PS) is strictly due to the cases of wrong predictions of correct performance. Thus, this PS represents the number of good answers that a participant believes he will obtain for each item presented. If a participant overestimates his own performance, his PS will be significantly higher than his real performance (i.e., the RS).

For the anosognosia score (AS), we calculatedthe discrepancy between the RS and the newly calculated PS.

Design of the scores

The DRS exhibits an inconvenience in its subscales: The total scores differ, which makes their comparison awkward when summed. To give each subscale the same importance in the DRS overall score, we used the weighted mean for the RS rather than for the PS. Thus, we corrected each subscale score by their respective number of items and converted it into percentages to aid readability. For example, the total score for the Attention subscale was divided by 37, which corresponds to the maximum score for this subscale, and it was then multiplied by 100 to obtain a percentage.

Finally, all the corrected subscales scores were averaged to obtain the weighted mean for the overall score of DRS for the RS and the PS. All analyses were conducted with all scores in terms of the percentage of good answers.

Stage of dementia

Based on the MMSE results, we formed three groups from the 97 patients. The groups differed in the presence and severity of dementia based on the work of Feldman and Woodward [47], Vellas et al. [48] and Reisberg et al. [49]. 28 patients formed the mild dementia (MiD; 21–26 MMSE) group, 30 patients formed the moderate dementia (MoD; 16–20 MMSE) group, and 39 patients formed the moderately severe dementia (MSD; 10–15 MMSE) group.

Statistical analysis

We studied the three groups as described previously (MiD, n = 28; MoD, n = 30; MSD, n = 39).

We used a Pearson Chi-square to ensure that the three groups were homogeneous.

We applied a one-factor ANOVA by group (independent). Post-hoc Bonferroni tests were applied if necessary. The significance level was set at p < 0.05 for all of the tests.

We employed a Pearson’s correlation coefficient to examine the relationship between the RS and the AS in our sample and to potentially determinate the neuropsychological correlates of cognitive anosognosia.

We conducted regression analysis for global AS to highlight potential neuropsychological predictors.

RESULTS

Description of the sample

The sample for analysis consisted of 97 patients divided into the aforementioned three groups. As expected, the groups significantly differed with respect to MMSE scores.

These three groups did not differ in terms of gender (χ² (2, n = 97) = 0.742, p = 0.690) or in terms of school graduation (χ² (2, n = 97) = 9.203, p = 0.0524) [50]. The clinical data are summarized in Table 1.

The groups were not different in terms of age (MiD versus MoD, p = 0.684; MoD versus MSD, p = 1.00; MiD versus MSD, p = 0.110).

Anosognosia and the severity of dementia

The anosognosia scores (AS) varied depending on the groups. The comparison between the MiD and MSD groups reached significance for all AS with the exception of the Memory subscale (MiD versus MSD, p = 0.067). In contrast, the difference between the MiD and MoD groups was only significant for the Memory AS. Finally, only the Construction and Conceptualization subscales showed significant differences between the MoD and MSD groups for AS.

All of the results regarding the overall scale and subscales of the DRS are shown in Table 1 and Fig. 1. All of the scores were compared across the three groups, i.e., the MiD (n = 28), MoD (n = 30) and MSD (n = 39) groups.

Anosognosia and overall cognitive functioning

A Bonferroni-corrected t-test revealed that the MiD and MoD groups exhibited similar performances for RSs (p = 0.299), PSs (p = 1.00), and ASs (p = 0.127). Overall, the PS decreased only in the MSD group (MoD versus MSD, p < 0.05 and MiD versus MSD, p < 0.05). The AS increased progressively with the worsening of dementia (i.e., the MiD group differed from the MSD group, p < 0.0001).

Anosognosia and process-specific domains

The comparison between the MiD and MoD groups revealed no significant differences in the scores of any subscale with the exception of the Memory subscale.

Attention

The MSD group differed significantly from the other groups in terms of the RS (MiD versus MoD, p = 1.00). Regarding the PS, none of the groups differed from each other (MiD versus MoD p = 0.997; MoD versus MSD, p = 0.064; MiD versus MSD, p = 0.627). Regarding the AS, only the comparison between the MiD and MSD groups was significant (MiD versus MoD, p = 0.522; MoD versus MSD, p = 0.423).

Initiation

The RS differed between the MSD group and the two other groups (MiD versus MoD, p = 1.00). Regarding the PS, only the comparison between the MoD and MSD groups was significant (MiD versus MoD, p = 0.997; MiD versus MSD, p = 0.252). Regarding the AS, the MiD-MSD comparison was significant (MiD versus MoD, p = 0.273; MoD versus MSD, p = 1.00).

Construction

Comparisons between the MiD and MSD groups revealed significant differences in the RS (MiD versus MoD, p = 1.00; MoD versus MSD, p = 0.085) and the AS (MiD versus MoD, p = 0.522). The MoD group differed from the MSD group in terms of the AS (p < 0.05). The other comparisons were not significant.

Conceptualization

Regarding the RS and the AS, the MSD group differed significantly from the two other groups (p < 0.01). None of the PS comparisons were significant (MiDversus MoD, p = 1.00; MoD versus MSD, p = 0.134; MiD versus MSD, p = 0.361).

Memory

The profile of Memory scores was singular. All RS comparisons were significant, including that between the MiD and MoD groups (p < 0.001). Regarding the PS, the MSD group differed significantly from the two other groups (MiD versus MoD, p = 1.00). Only the AS differed between the MiD and MoD groups, and no significant effects were observed in the other comparisons (MiD versus MSD, p = 0.067; MoD versus MSD, p = 1.00).

Correlates of cognitive anosognosia in AD

The correlations between the RS and the AS are important for highlighting the potential neuropsychological correlates of cognitive anosognosia. As shown in Table 2, the total weighted mean AS was correlated with all of the cognitive processes involved in the DRS, with a very narrow range of correlations from –0.36 to –0.45.

Conversely, the anosognosia scores were correlated with the overall neuropsychological performance scores (r < –0.33, p < 0.01). Specifically, they were correlated with the Conceptualization AS (r = –0.56, p < 0.001) but not with the Memory AS (r = –0.10, p = 0.32). All of the processes involved in the five subscales were correlated with the anosognosia scores for the Attention, Initiation, Construction, and Conceptualization subscales (ranging from –0.18 to –0.56). Only the Memory AS was very weakly correlated with the cognitive processes, with correlation coefficients ranging from –0.03 to –0.06.

Predictors of cognitive anosognosia

The results are presented in Table 3. In the linear regression analysis, there was a significant relationship between total DRS AS and categories’ RSs in the overall model (adjusted r² = 0.278, F(5,91) = 8.39, p < 0.0001). Specifically, higher scores for global anosognosia were associated only with poor memory processes (t = –2.03, β = –0.211, p < 0.05). Memory RS was the only variable that predicts total AS.

DISCUSSION

The aim of this study was to highlight that anosognosia in AD varies across cognitive domains as assessed with standardized tools based on performance predictions and that dementia path and levels of anosognosia are probably closely related.

The first and most salient result was the lack of significant relationships between the MiD and MoD groups for almost all of the scores (i.e., RS, PS, and AS) for both the level of overall functioning and for the specific processes with the exception of Memory. We obtained strong plateau effects between the groups with mild and moderate dementia in terms of the scores for anosognosia, actual performances and predictions.

The second important result involved the Memory subscale. Regardless of the score in question (i.e., RS, PS, or AS), the profiles of patient responses were vastly different and, indeed, opposite compared with the profiles of the processes. These differences indicate a cleavage between memory and other cognitive functions, as initially highlighted by Antoine et al. [27].

Overall performance and the severity of dementia

The MiD and MoD groups did not exhibit differences in their actual performance for four of the five subscales or for the total score. Regarding the severity of dementia, only the MSD group exhibited worse real performances (RS) relative to the other groups, but this group was also the only group that predicted worse performance (PS), i.e., a lower percentage of good answers. These results suggest that the ability to predict one’s performance is bound to one’s own cognitive capacities at the time, but this ability is affected only when severe impairment is present. Thus, these findings are consistent with those of previous research and show that awareness requires the abilities to monitor ongoing performance and to form meta-representations and, thus, requires intact complex cognitive processes [51]. Worse dementia is associated with greater deterioration of these abilities, which in turn, causes difficulties in the estimation and judgment of abilities (for review, see [52, 53]).

Specifically concerning the phenomenon of anosognosia, the AS increased with the progression of dementia because only the MiD and the MSD groups significantly differed from each other; this score more than doubled from one extreme to the other. Our findings confirm those of many previous studies: Specifically, anosognosia worsens with the evolution of dementia [52]. However, it is also important to note that because of this plateau effect, the severity of dementia appears to be only partially responsible for the appearance of this phenomenon, as previously shown in the literature [8].

Process specific

Real score

As mentioned previously, the MiD and MoD patients presented the same overall cognitive functioning in terms of the first four subscales of Attention, Initiation, Construction, and Conceptualization but differed in terms of Memory. Thus, we observed that the scores decreased significantly only beginning with the MSD group, which created a split in performances on the Attention, Initiation, and Conceptualization subscales [54]. Regarding the Construction subscale, this split did not appear; rather, performances decreased more slowly and gradually, which may have been due to the very high standard deviation that resulted from the 6-point subscale. Therefore, the items of the DRS appear to be responsive at high levels of dementia [55].

Memory was the only subscale that marked the different levels of dementia. Memory processes appear to be altered early in the disease and to exhibit obvious degradation before other functions as the disease progresses. This result is consistent with the literature regarding memory in AD (for a review, see [56, 57]) and confirms the findings that have suggested a distinction between memory and other cognitive processes [27].

Predicted score

Regarding the predictions, among the majority of the patients, the estimate of their performance did not differ significantly between groups in the Attention, Construction, or Conceptualization subscales because all patients predicted scores of total or near-total success (all of the percentages were greater than 85%). These processes are less influenced and, therefore, less altered by early AD [54, 58]. Then, patients might have a better understanding of their processes; thus, they could easily assess their functioning.

Regarding the Initiation subscale, one comparison remained significant between the MoD and MSD groups. Despite the identical predictions for the MiD and MSD groups, the MoD group was distinguished by a superior estimate of its performance. This subscale encompasses one particular principal item, i.e., fluency, which is the only open item without dichotomous and multiple-choice answers. Predictions for this item could be more difficult compared to the others because this item is based on a subjective given quantity of words to estimate. Thus, patients with little anosognosia (and thus mild dementia) would be more cautious and predict much lower expected performances.

The patients offered lower predictions for memory only when dementia was substantially worsened. This was the only subscale for which the predicted percentage of good answers varied with the level of dementia. However, the profiles of the predictions did not follow the decrease in memory processes between mild and moderate dementia; similar results have been reported in previous research [27].

Anosognosia score

Finally, disregarding Memory, we revealed two patterns for the evolution of anosognosia scores. The first pattern was distinguished by its dimensions of Attention and Initiation, and the second was distinguished by its Construction and Conceptualization components. The first pattern exhibited a linear and very progressive increase in anosognosia with dementia deterioration, and the second pattern implied a break between the MiD-MoD plateau effect and the MSD group. Nevertheless, it is important to emphasize that anosognosia critically worsened with moderately severe dementia and, thus, with a major cognitive impairment, which supports the literature on anosognosia in AD [7 , 11].

The main result for the AS of Memory was related to the absence of a plateau effect in the first two groups, i.e., the MiD and MoD groups. From moderate dementia, the level of anosognosia no longer appeared to increase with the progress of the disease and, thus, with memory deterioration, which is consistent with the literature [59, 60]. Anosognosia of memory impairment stabilizes while the anosognosia of other cognitive functions exhibits major increases. Our results appear to confirm the hypothesis of memory as a maintenance factor more than as a primary cause of anosognosia, which is supported by Agnew and Morris [41].

Neuropsychological correlates and predictors of cognitive anosognosia

The correlations between the RS and the AS were interesting in the sense that each cognitive process assessed in the DRS is involved in the expression of cognitive anosognosia in all of these processes with the exception of memory. No cognitive process influenced the anosognosia of memory deficits, whereas memory processes were related to all of the global and specific anosognosia scores, and these findings overlap with those of Antoine et al. [27]. Overall neuropsychological functioning does not appear to be at the origin of this phenomenon.

All cognitive processes were moderately correlated with the total AS. No process was particularly noteworthy with respect to this correlation. Our analysis only demonstrated that the RS of memory was a predictor of global anosognosia. In accordance with previous studies, memory performance appears to impact the presence of anosognosia [39 , 62]; however, our results are not powerful enough to reach definitive conclusions but instead provide clues regarding processes involved in this phenomenon.

Memory disconnection

In this study, we highlighted the dissociation between memory and other cognitive processes at the levels of both actual performance and predictions and also in terms of the anosognosia process. This disconnection supports the hypotheses that different mechanisms underlie anosognosia of memory on the one hand and those of the other cognitive functions on the other hand.

First, anosognosia must be understood in terms of its relationship with a “specific object” [13, 38], which means that every object, that is to say, each process that is affected by anosognosia, such as memory, must be considered and studied as a full-fledged phenomenon that is potentially connected to others. Thus, each process can be impaired separately from the others, which could explain why memory can be precociously affected without other repercussions. Moreover, anosognosia as measured by performance-prediction discrepancies should be regarded as a specific form of anosognosia [63] and a form that worsens with the advance of dementia.

From this perspective, some neuropsychological models have proposed that anosognosia operates on different levels from the sensory and perceptual levels to the high cognitive processes (i.e., a “complex” level) wherein the heterogeneity of anosognosia is the basis of the theory [64, 65]. Recently, Morris and Mograbi [66] proposed a revised version of the Cognitive Awareness Model [42 , 51], which splits memory into different hierarchical modules that manage the performance monitoring of sensory input that is processed and compared with personal semantic and autobiographical data. Different modules involve several types of memory such that many possibilities for impairment exist and lead to the different expressions of anosognosia [67].

Anosognosia nurtures a special relation with the severity of dementia without this being a cause-effect link. Indeed, dementia worsens long before the appearance of anosognosia for most cognitive processes. In this context, this type of anosognosia may be understood as a consequence of the impairment of complex abilities, such as monitoring or meta-representation.

Relying on the Cognitive Awareness Model and previous results, the main components of anosognosia in the early stage of AD may be the failed functioning of the memory systems used for the management of incoming information and self-assessment.

However, we also noted some limitations. The lack of difference between the MiD and MoD groups is consistent with the notion that the DRS may not be the most relevant battery for discriminating the early stages of dementia [68]. Despite this defect, we chose the DRS because of its characteristics of simplicity of understanding and multidimensionality of assessment. Moreover, we observed a ceiling effect for the RS and the PS for the Attention items, but the AS still increased. The presence of an effect for predictions about Initiation can be explained by differences in the evaluation content relative to other items (i.e., the naming of supermarket items). These results suggest that the use of finer assessments of executive functions is needed to distinguish the actual involvement of those functions.

CONCLUSION

Our study sought to characterize the heterogeneity of cognitive anosognosia in AD using a paradigm involving predictions of performance. The main results confirmed the multidimensionality of the phenomenon and its variability with the stage of dementia and particularly implicated memory processes.

Studying more specific processes with varied and purer neuropsychological tests would enable us to establish clearer connections between anosognosia and cognitive impairments over the course of dementia’s evolution. The establishment of such connections would highlight the correlates that explain the late onset of the majority of processes. Purer tests may also help to understand the disconnection of memory and its early involvement in this phenomenon.

Eventually, we will identify the mechanisms that underlie anosognosia to enable the development of tools and simple and ecological measures for all stages of the care circuit. Thus, through these measures, the health team and relatives will be able to know what the patient feels and perceives regarding the situation, which will improve medical and social support requirements based on the ability to understand the patient’s experience of the disease.

Finally, a larger sample of patients would allow us to look at the evolution of the phenomenon of anosognosia closer to the course of dementia. That would enable us to refine the progression curve of this symptom throughout the disease and abandon fixed categories of dementia. Future research should address the size constraints identified in this study. Moreover, a substantial sample of patients will be useful for confirming the results, as it will furnish sufficient statistical power with regard to the analyses.

Footnotes

ACKNOWLEDGMENTS

This work was supported by France Alzheimer and the Conseil Départemental du Nord. This work was developed through LabEx (excellence laboratory, program investment for the future), DISTALZ (Development of Innovative Strategies for a Transdisciplinary Approach to ALZheimer disease) and the MESHS (Maison Européenne des Sciences de l’Homme et de la Société, Lille, France).

Authors’ disclosures available online ().

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