domain: shs scco

text:
Jacus J-P

Jean-Pierre Jacus
email: jeanpierrej@chi-val-ariege.fr

Awareness dimensions and associated factors in Alzheimer's disease

Keywords: Alzheimer's disease, Apathy, Awareness assessment method, Awareness dimensions, Depression

Awareness dimensions and associated factors in

Alzheimer's disease

INTRODUCTION

Awareness disturbances are core features in Alzheimer's disease (AD) prematurely affecting patient autonomy and causing early placement in structured living environments [START_REF] Jacus | Modelling awareness in Alzheimer's disease[END_REF] . This symptomatology is heterogeneous and various terms to refer to different conceptualizations have been used to describe it [START_REF] Jacus | Awareness Disorders in Alzheimer's Disease and in Mild Cognitive Impairment[END_REF] . Anosognosia was the first term used. It involves cognitive conceptualizations suggesting a main role of metacognition in this phenomenon [START_REF] Mcglynn | Unawareness of deficits in neuropsychological syndromes[END_REF] . Denial is more often used in psychoanalytical conceptualizations, in reference to the unconscious refusal to acknowledge a too painful reality [START_REF] Weinstein | Denial/unawareness of impairment and symbolic behaviour in Alzheimer's disease[END_REF] . Insight, especially in its broader form, is a psychiatric viewpoint involving judgments and the nature of patients' consciousness of their disorders, in particular delusions and hallucinations. In its narrower form ("insight into dementia"), awareness is conceptualized as the basic perception of impairments [START_REF] Marková | Insight in psychiatry[END_REF] . Other conceptualizations have been proposed, but it is known that none of them are able to explain the heterogeneity of awareness disturbances in AD [START_REF]The construction of awareness in early-stage Alzheimer's disease: A review of concepts and models[END_REF] . This is why Clare and colleagues [START_REF]The construction of awareness in early-stage Alzheimer's disease: A review of concepts and models[END_REF] developed a bio-psychosocial model suggesting that awareness disturbances relate to a selfadjustment as resulting from biological, psychological and social changes with the progress of the disease. Subsequently phenomenological models have considered the disease experience expressed by the patient in order to take the heterogeneity of awareness into account by way of different mechanisms or processes (comparison between past and present, metacognition, etc.), domains (communication, memory, autonomy, etc.) and modes of expression (denial, bewilderment, causal attribution, etc.) [START_REF] Mayelle | Awareness of Self and Disease Assessment: Development and Validation of a Subjective Measure in People with Alzheimer's Disease[END_REF] .

Except for bio-psychosocial and phenomenological approaches, awareness in AD is classically assessed using three methods [START_REF] Mayelle | What" and "How": A New Perspective for Understanding Unawareness in Alzheimer's Disease Through a Combination of Two Perspectives[END_REF] . The patient-caregiver discrepancy method, using the caregiver ratings as the reference by subtracting the patient ratings from them. The scales using this method explore different domains or dimensions of awareness, such as cognitive or behavioural disturbances. The clinical rating method use a structured interview with the

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patient concerning different domains of impairment in which the clinician rating is used as the reference. The prediction of performance discrepancy method in which the scores obtained on the test used are the reference to be compared to the predictions. The domains of awareness explored are those of the test used.

These three methods mainly focus on awareness dimensions, which are presented as the first aspect to consider to understand patients with impaired awareness of their disorder [START_REF] Mayelle | What" and "How": A New Perspective for Understanding Unawareness in Alzheimer's Disease Through a Combination of Two Perspectives[END_REF] .

However, using these methods, many studies have reported heterogeneous results, attributed mainly to the different assessment methods, domains of awareness and disease stages studied [START_REF] Marková | Insight in psychiatry[END_REF] . Alongside, awareness seems to be associated with disease stage [START_REF] Starkstein | Anosognosia in Alzheimer's disease: Diagnosis, frequency, mechanism and clinical correlates[END_REF] . In a previous study [START_REF] Jacus | Modelling awareness in Alzheimer's disease[END_REF] ,

we recently suggested a model of awareness in AD using disease severity as an exposure factor (risk factor of impaired awareness) and integrating these three main assessment methods. The results showed that greater awareness was associated with greater depression and lower apathy for all the scales relating to the patient-caregiver discrepancy and clinical rating methods. Greater awareness was associated with more heterogeneous factors (apathy and especially cognition) in the prediction of performance discrepancy method.

Nevertheless, these results did not take into account the role of the different dimensions of awareness (i.e. the different sub-scales or dimensions included in each scale used). Because awareness is heterogeneous, one disturbance can be recognized while another can be misunderstood by the patient, and thus it is relevant to take into account their impact in daily living. Therefore, using the same patient data as in our previous study [START_REF] Jacus | Modelling awareness in Alzheimer's disease[END_REF] , our objective was here to evaluate the role of these dimensions and their associated factors.

Considering the heterogeneity of awareness disturbances in AD [START_REF] Jacus | Modelling awareness in Alzheimer's disease[END_REF][START_REF] Marková | Insight in psychiatry[END_REF][START_REF] Mayelle | What" and "How": A New Perspective for Understanding Unawareness in Alzheimer's Disease Through a Combination of Two Perspectives[END_REF] , we hypothesized that in addition to the factors (apathy-depression in particular) usually associated with global awareness scores [START_REF] Jacus | Modelling awareness in Alzheimer's disease[END_REF][START_REF] Starkstein | Anosognosia in Alzheimer's disease: Diagnosis, frequency, mechanism and clinical correlates[END_REF][START_REF] Azocar | The Association Between Impaired Awareness and Depression, Anxiety, and Apathy in Mild to Moderate Alzheimer's Disease: A Systematic Review[END_REF] , there would be specific factors associated with the different awareness dimensions (i.e. a cognitive awareness sub-scale will be associated with cognitive NEUROL-D-20-00438R2 functions, a subtest on awareness of activity of daily living abilities will be associated with autonomy in daily living, and so on).

MATERIALS AND METHOD

Participants

Sixty-one Alzheimer patients (mean age=81.3; % female=50.8) recruited from a memory clinic and diagnosed following the National Institute for Aging and the Alzheimer's Association working group recommendations [START_REF] Mckhann | The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging and the Alzheimer's Association workgroup on diagnostic guidelines for Alzheimer's disease[END_REF] were included in this study. They constituted the patient group of our previous study [START_REF] Jacus | Modelling awareness in Alzheimer's disease[END_REF] that also included healthy controls.

Evaluation tools

AD patients were assessed using four awareness scales related to the three main assessment methods presented above [START_REF] Jacus | Modelling awareness in Alzheimer's disease[END_REF][START_REF] Starkstein | Anosognosia in Alzheimer's disease: Diagnosis, frequency, mechanism and clinical correlates[END_REF] . (a) For the patient-caregiver discrepancy method:  The Patient Competency Rating Scale -PCRS [START_REF] Prigatano | Cognitive dysfunction and psycho-social adjustment after brain injury[END_REF] including the sub-scales: "Activities of Daily living (ADL)", "Cognition", "Interpersonal Relations" and "Emotions". The PCRS asks the participant and a relative the same 30 questions on the participant's ability to perform various daily living activities. Levels of awareness on the overall scale and each sub-scale are assessed by subtracting the participant's rating from the relative's rating.

Positive scores indicate greater awareness.

 The Anosognosia Questionnaire for Dementia -A-QD [START_REF] Starkstein | A diagnostic formulation for anosognosia in Alzheimer's disease[END_REF] including "Cognitive" and "Behavioral disturbances" sub-scales, designed on the same principle as the PCRS.

Awareness is scored in a similar manner to the PCRS, but negative scores indicate greater awareness.

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(b) For the clinical rating method, we used the Self-Consciousness Scale in AD -SCSAD [START_REF] Gil | Selfconsciousness and Alzheimer's disease[END_REF] , a structured patient interview involving seven dimensions of self-consciousness: "Identity", "Cognitive disturbances", "Affective state", "Bodily representation", "Prospective memory", "Introspection abilities" and "Moral judgments". Higher scores indicate greater awareness.

(c) For the prediction of performance discrepancy method, we used the Multidimensional Isomorphic Simple Awareness Assessment -MISAware [START_REF] Antoine | Awareness of deficits in Alzheimer's disease patients: Analysis of performance prediction discrepancies[END_REF] which requires participants to predict their neuropsychological performance on the Dementia Rating Scale -DRS [START_REF] Mattis | Mental status examination for organic mental syndrome in the elderly patient[END_REF] . The self-ratings are then compared to those obtained on the DRS, which includes five sub-scales: "Attention", "Initiation", "Conceptualization" relating to executive functioning, "Construction" relating to visuo-spatial functioning, and "Memory" relating to mnesic functioning. Lower scores indicate greater awareness.

AD patients also completed the Mini Mental State Examination -MMSE [START_REF] Folstein | Mini Mental State. A practical method for grading the cognitive state of patients for the clinician[END_REF][START_REF] Hugonot-Diener | The Mini Mental Status Examination or MMSE consensual version of GRECO[END_REF] and the Frontal Assessment Battery -FAB [START_REF] Dubois | The FAB: A frontal assessment battery at bedside[END_REF] for cognitive performances. We used the Instrumental Activities of Daily Living scale -IADL [START_REF] Lawton | Assessment of older people: self-maintaining and instrumental activities of daily living[END_REF] , scored by a relative, to assess autonomy. Most patients (n=55) were also evaluated using the Free and Cued Recall Test -FCRT [START_REF] Ergis | L'exploration des troubles de la mémoire épisodique dans la maladie d'Alzheimer débutante au moyen d'une épreuve de rappel indicé[END_REF] , assessing episodic memory. For all tasks, higher scores indicate better abilities.

Levels of depression and apathy, known to be involved in awareness in AD, were assessed [START_REF] Starkstein | Anosognosia in Alzheimer's disease: Diagnosis, frequency, mechanism and clinical correlates[END_REF] . We used the Geriatric Depression Scale -GDS (completed by the patient) [START_REF] Clément | Development and contribution to the validation of a brief French version of the Yesavage Geriatric Depression Scale[END_REF] , in which higher scores indicate greater depression, and the Apathy Evaluation Scale -AES [START_REF] Marin | Reliability and validity of the apathy evaluation scale[END_REF] (completed by a relative: AES Relative and the clinician: AES Clinician ), in which lower scores indicate greater apathy.

Statistical analyses

The statistical analyses were carried out using R software (version 4.0.2) (generalhoslem, Hmisc, and questionr packages). In order to identify the factors associated with the different

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awareness scales or sub-scales and disease stage, we performed a backward manual regression for each of them, using the following variable selection method . To perform the regressions there must be no missing data. The MMSE score was used as the exposure factor determining the stage of AD [START_REF] Jacus | Modelling awareness in Alzheimer's disease[END_REF][START_REF] Hugonot-Diener | The Mini Mental Status Examination or MMSE consensual version of GRECO[END_REF] and was always maintained in the model. Demographics (age, educational level in years and gender), autonomy (IADL), executive functioning (FAB), apathy (AES) and depression (GDS) were univariately tested with each of the four global measures of awareness and for each of their sub-scales or dimensions. The cut-off was set at p<0. 25 for this preliminary model in order to avoid excluding future significant variables.

Each interaction between the exposure factor (MMSE) and the variables retained in the preliminary model was univariately tested with the dependent variable. The cut-off was also set at p<0. 25. Once the preliminary model was established with the selected interactions, the backward process began, removing one by one the non-significant interactions (p<0.05), beginning with those having the highest p-values. If an interaction was found to be significant, therefore the factor interacting with the exposure factor was maintained in the model even if it was non-significant. The same process was performed with the nonsignificant main factors (p<0.05). When removal of a main factor impacted at least 15% of the exposure factor estimate (relative variation: -), the factor was considered as a potential confounder and was therefore maintained in the model, given that this relative variation is significant when it falls between 10 and 20% [START_REF] Jacus | Modelling awareness in Alzheimer's disease[END_REF] . The analysis was discontinued when there were no remaining significant factors. Confounding factors and the exposure factor (MMSE) remained in the final model. Because some sub-scales did not comply with the validity conditions for linear models, we used logistic multivariate models, setting a cut-off at the median value of the sample for each dependent variable a (overall a Given that a logistic model is by definition binary.

awareness scales and sub-scales). Finally, we ascertained each model by the Hosmer and Lemeshow test (² non-significant) b .

Because the conditions of parametric correlations (Pearson) were not fulfilled, we calculated non-parametric correlations between the available variables and predictions on the MISAware as well as self and caregiver's awareness reports, in order to have a better understanding of the logistic models.

RESULTS

We reported in Table 1 the demographic, cognitive, behavioural and awareness patient data.

Logistic models for the overall awareness scales and sub-scales

These models are presented in Table 2.

Because logistic models were used in the present study while we used linear models in our previous study [START_REF] Jacus | Modelling awareness in Alzheimer's disease[END_REF] , we checked that there were globally the same associations with the overall awareness scales.

While the total PCRS scores evidenced associations with the GDS and AES Relative in our previous study using a linear model [START_REF] Jacus | Modelling awareness in Alzheimer's disease[END_REF] , the total score was here associated with the same factors and the MMSE using a logistic model (GDS: OR=0.52, CI95%=0.32-0.75, p=0.002; AES Relative : OR=0.89, CI95%=0.81-0.96, p=0.005; MMSE: OR=1.26, CI95%=1.02-1.60, p=0.004). All the PCRS sub-scales were associated with the GDS and/or the AES Relative- Clinician . However, the "Interpersonal Relations" logistic model did not comply with the Hosmer and Lemeshow test (²=16.48, p=0.03).

While the total A-QD score evidenced associations with the GDS and AES Relative in our previous study using a linear model [START_REF] Jacus | Modelling awareness in Alzheimer's disease[END_REF] , the total score remained associated with the same b The Hosmer-Lemeshow test is a statistical test for goodness-of-fit for logistic regression models.

factors using a logistic model. Nevertheless, only the "Cognition" sub-scale was associated with the GDS and the AES Relative . For the "Behavioral disturbances" sub-scale, there was merely a significant trend for both GDS and AES Relative (OR=0.76, CI95%=0.55-0.99, p=0.059; OR=0.94, CI95%=0.87-1.00, p=0.066 respectively).

Only three of the seven dimensions in the SCSAD proved discriminant and were useable: "Cognitive disturbances ", "Introspection abilities" and "Moral judgments". The others showed no variance and always reached the top scores.

While the total SCSAD score evidenced associations with the GDS and AES Clinician in our previous study using a linear model [START_REF] Jacus | Modelling awareness in Alzheimer's disease[END_REF] , the total score was here only associated with the AES Relative and the AES Clinician using a logistic model (AES Relative : OR=0.89, CI95%=0.80-0.97, p=0.019; AES Clinician : OR=0.87, CI95%=0.74-0.99, p=0.050). The three available dimensions were associated with the GDS and/or the AES Relative-Clinician and also with demographic variables.

While the total MISAware evidenced associations with the MMSE, AES Relative and FAB in our previous study using a linear model [START_REF] Jacus | Modelling awareness in Alzheimer's disease[END_REF] , the total score was here significantly associated with the MMSE, AES Relative and gender (female) using a logistic model (MMSE: OR=0.68, CI95%=0.51-0.85, p=0.002; AES Relative : OR=0.84, CI95%=0.72-0.94, p=0.003; gender (female): OR=0.52, CI95%=1.19-2.85, p=0.038). The "Attention", "Initiation" and "Conceptualization" sub-scales were associated solely with the FAB, except for the "Attention" sub-scale, also significantly associated with age. The analysis failed to show significant factors associated with the "Construction" and "Memory" sub-scale scores.

Nevertheless, in a complementary analysis introducing the FCRT (administered only to 55 patients), we observed that the "Memory" sub-scale showed a significant association with total recall (p=0.020), the GDS (p=0.040) and interactions between GDS and MMSE (p=0.033).

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Non-parametric correlations (Table 3)

For non-parametric correlations across the available factors, including self/relative reports for PCRS, A-QD and MISAware predicted scores, the significance cut-off was set at p<0.01 because there were twenty-five (25) correlations. The predicted MISAware scores correlated with the MMSE and AES Clinician (ρ=0.46, p=0.0002; ρ=0.35, p=0.0062 respectively). Relative reports for the PCRS and for A-QD correlated with IADL (ρ=0.46, p=0.0002; ρ=-0.41, p=0.0010 respectively), AES Relative (ρ=0.61, p<0.0001; ρ=-0.66, p<0.0001 respectively) and AES Clinician (ρ=0.33, p=0.0099; ρ=-0.33, p=0.0087 respectively). Finally, self-reports for the PCRS and A-QD correlated solely with the GDS (ρ=-0.58, p<0.0001; ρ=0.45, p=0.0003 respectively).

DISCUSSION

Our present results show that the linear models used in our previous study [START_REF] Jacus | Modelling awareness in Alzheimer's disease[END_REF] and the subsequent logistic models found the same overall associations with only minor differences.

Concerning both the patient-caregiver discrepancy and the clinical rating methods, our results suggest that, whatever the domain assessed, greater awareness is associated with greater depression and/or lower apathy. Contrary to our hypothesis relating to the role of specific factors associated with the domains assessed, cognitive awareness sub-scales did not show any associations with cognitive functions, such as the MMSE or FAB scores, when using these methods.

Concerning the prediction of performance discrepancy, the total MISAware scores did not evidence the same associations as three of its sub-scales (MMSE, gender and apathy versus executive functioning measured with the FAB only for "Attention", "Initiation" and "Conceptualization"). Two sub-scales showed no associations, but after introducing an additional explanatory variable assessing episodic memory measured by the FCRT, NEUROL-D-20-00438R2 associations with the "Memory" sub-scale were observed. This suggests that awareness could be associated with specific domains assessed by different sub-scales, highlighting the importance of awareness dimensions when using this method.

Our results still suggest a distinction between a referential based on a test rating and another based on a human rating (clinician or relative). This was suggested in our previous study [START_REF] Jacus | Modelling awareness in Alzheimer's disease[END_REF] and seems to be congruent here, using only patient data for overall awareness scales and subscales. The referential based on a test rating seems relatively congruent with cognitive models focusing on the role of metacognition, because awareness domains proved to be associated with specific factors assessed by the DRS. Thus, the MISAware sub-scales "Attention", "Initiation" and "Conceptualization" mainly involving executive functioning were associated with the FAB which also relates to executive functions. The MISAware "Memory" sub-scale was associated with the FCRT assessing episodic memory. Finally, the MISAware "Construction" sub-scale relating to the visuo-spatial domain failed to show any significant association, perhaps because we did not introduce a visuo-spatial test in the logistic model.

The referential based on a human rating yields results congruent with the conceptualization of awareness proposed by Marková [START_REF] Marková | Insight in psychiatry[END_REF] , in its narrower form ("insight into dementia"). This author considers this narrower form as determined only by the patient's perception of impairment. Therefore, insight into dementia is unidimensional, so that the only dimension of awareness is that of the impairment itself, whatever the domain concerned.

Depression scores correlated only with self-reports, which could be understood as an underestimation of their abilities by patients with greater depression. This interpretation is congruent with research reporting that depression, anxiety, and certain personality traits influence subjective cognitive complaints [START_REF] Ryu | Self-and informantreported cognitive functioning and awareness in subjective cognitive decline, mild cognitive NEUROL-D-20-00438R2 impairment, and very mild Alzheimer disease[END_REF] . Autonomy and apathy scored by relative and clinician correlated with relative reports. Autonomy and apathy scored by a relative lacked relevance because the person scoring was also the one who scored in the relative awareness NEUROL-D-20-00438R2 report. However, the correlation between relative reports and apathy scored by the clinician was more relevant. Various studies have reported associations between poorer awareness and greater apathy [START_REF] Jacus | Modelling awareness in Alzheimer's disease[END_REF][START_REF] Starkstein | Anosognosia in Alzheimer's disease: Diagnosis, frequency, mechanism and clinical correlates[END_REF][START_REF] Starkstein | Anosognosia Is a Significant Predictor of Apathy in Alzheimer's Disease[END_REF] . There is a growing body of evidence that apathy and impaired awareness are common manifestations in AD. Clinically, Starkstein et al. [START_REF] Starkstein | Anosognosia Is a Significant Predictor of Apathy in Alzheimer's Disease[END_REF] reported that anosognosia predicts apathy in AD. From a neuro-anatomical viewpoint, both apathy and impaired awareness involve the anterior cingulate cortex [START_REF] Starkstein | Anosognosia Is a Significant Predictor of Apathy in Alzheimer's Disease[END_REF] , although it has been reported that awareness deficit, but not apathy, correlates with atrophy in the dorsal anterior cingulate cortex [START_REF] Guerrier | Involvement of the Cingulate Cortex in Anosognosia: A Multimodal Neuroimaging Study in Alzheimer's Disease Patients[END_REF] . Finally, apathy is consensually divided into three dimensions: loss of interest, loss of initiative and affective blunting [START_REF] Mulin | Diagnostic Criteria for Apathy in Clinical Practice[END_REF] , which could influence relative ratings and clinical ratings alike, explaining why apathy was also associated with the SCSAD in the different logistic models. Apathy scored by the clinician was also correlated with patient predictions using the MISAware. This could explain the associations between the apathy scores and the total MISAware score, because an overestimation of abilities could be associated with apathy.

Indeed, an apathetic patient would have a lack of sensitivity towards his deficits and inabilities. Finally, one possible relevant question is whether impaired awareness is a main component of apathy.

Several limitations should be underlined concerning this research. The sample size could be criticised given to our statistical strategy derived from epidemiological methods. There was collinearity between the factors entered into the model, and the model did not reflect all the variables known to be involved in awareness. Some sub-scales in awareness scales such as the SCSAD include a few items yielding unsustainable results. In addition, several models used for the awareness sub-scales did not previously suit linear modelling, requiring logistic models, leading to a loss of information probably explaining the slight differences between linear and logistic models for the global scales (see 3.1). This is why we kept exactly the same patient data as that used in our previous study [START_REF] Jacus | Modelling awareness in Alzheimer's disease[END_REF] , to confirm the same overall associations,

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Page 20 sur 20

Table 1 : Demographic, cognitive, behavioural and awareness patient data.

 1 Self-Consciousness scale in Alzheimer's disease.

	1 Lowest score indicates lowest cognitive performances, lowest level of depression, lowest level of apathy and
	lowest level of awareness (most impaired awareness).
	AES: Apathy Evaluation Scale (scored by a relative or the clinician); A-QD: Anosognosia Questionnaire for

Dementia; FAB: Frontal Assessment Battery; GDS: Geriatric Depression Scale; MISAware: Multidimensional Isomorphic Simple Awareness Assessment; MMSE: Mini Mental State Evaluation; PCRS: Patient Competency Rating Scale; Self Consciousness: Page 19 sur 20

Table 2 : Associated factors with awareness scales and sub-scales

 2

	1
	Awareness scales / sub-scales	GDS	AES Relative	AES Clinician	Others

Dementia; FAB: Frontal Assessment Battery; GDS: Geriatric Depression Scale; MISAware: Multidimensional 3 Isomorphic Simple Awareness Assessment; MMSE: Mini Mental State Evaluation; PCRS: Patient Competency 4 Rating Scale; SCSAD: Self-Consciousness scale in Alzheimer's disease.

Table 3 : Correlations across demographic, cognitive (including autonomy), behavioural (including mood) variables, self/relative awareness reports and predictions

 3

	MMSE	IADL a	GDS	AES Relative	AES Clinician
	PCRS patient rating

Acknowledgments:

The authors would like to thank and Mrs Angela VERDIER and Sarah LEYSHON for their linguistic and scientific assistance.

and to test the impact of these associations across the different domains of awareness assessed. Nevertheless, we did not anticipate at the time of our previous study [START_REF] Jacus | Modelling awareness in Alzheimer's disease[END_REF] that we would need to explore the role of awareness dimensions. Therefore, in the present study, some scales exploring behavioural disturbances, such as the NeuroPsychiatric Inventory [START_REF] Cummings | The Neuropsychiatric Inventory: assessing psychopathology in dementia patient[END_REF] , which could be associated with awareness in this domain, are lacking.

In conclusion, it appears that the role of awareness dimensions varies with the method used.

The patient-caregiver discrepancy and clinical rating methods do not evidence the role of awareness dimensions, while they are supposed to be focused on them [START_REF] Mayelle | What" and "How": A New Perspective for Understanding Unawareness in Alzheimer's Disease Through a Combination of Two Perspectives[END_REF] . In contrast, in the prediction-performance discrepancy method, awareness appears strongly associated with the domains assessed (as specific factors). Consequently, this method seems to be the most relevant to assess awareness dimensions in clinical practice. Nevertheless, these basic approaches are either too restricted to depression and apathy or mainly dependent on the domains assessed to obtain a broad understanding of awareness experienced by patients with AD in daily living. Thus, a phenomenological perspective proposing a person-centred approach would be more relevant to capture broader phenomena of awareness in AD [START_REF] Mayelle | Awareness of Self and Disease Assessment: Development and Validation of a Subjective Measure in People with Alzheimer's Disease[END_REF][START_REF] Mayelle | What" and "How": A New Perspective for Understanding Unawareness in Alzheimer's Disease Through a Combination of Two Perspectives[END_REF] .

The authors have no conflict of interest to report.


text:
Jean-Pierre Jacus
email: jeanpierrej@chi-val-ariege.fr

Amandine Mayelle

Virginie Voltzenlogel

Christine-Vanessa Cuervo-Lombard

Pascal Antoine

Jacus Jp

Cuervo-Lombard Cv

Modelling Awareness in Alzheimer's Disease

Keywords: Alzheimer's disease, Apathy, Awareness, Depression

Introduction

Awareness in Alzheimer's Disease (AD) is a broad and changing construct, varying with different approaches and the stage of the disease. These approaches mainly distinguish [START_REF] Starkstein | Anosognosia in Alzheimer's disease: Diagnosis, frequency, mechanism and clinical correlates[END_REF] explicit and (2) implicit measures, based on three methods usually used to assess awareness: (1a) patient-caregiver discrepancy, (1b) prediction of performance discrepancy, and [START_REF] Mayelle | Awareness of Self and Disease Assessment: Development and Validation of a Subjective Measure in People with Alzheimer's Disease[END_REF] clinical rating [START_REF] Starkstein | Anosognosia in Alzheimer's disease: Diagnosis, frequency, mechanism and clinical correlates[END_REF][START_REF] Mayelle | Awareness of Self and Disease Assessment: Development and Validation of a Subjective Measure in People with Alzheimer's Disease[END_REF]. Our objective was the development of a model of awareness in AD based on the different approaches of this phenomenon and disease severity.

Most studies reported increased frequency of impaired awareness as the disease progresses, so that disease severity appears as the main risk factor for impaired awareness [START_REF] Starkstein | Anosognosia in Alzheimer's disease: Diagnosis, frequency, mechanism and clinical correlates[END_REF][START_REF] Avondino | Heterogeneity of Cognitive Anosognosia and its Variation with the Severity of Dementia in Patients with Alzheimer's Disease[END_REF][START_REF] Horning | Insight in Alzheimer's disease and its relation to psychiatric and behavioral disturbances[END_REF].

These studies also reported specific associations with cognitive and behavioral executive dysfunctions [START_REF] Horning | Insight in Alzheimer's disease and its relation to psychiatric and behavioral disturbances[END_REF][START_REF] Marková | Phenomena of awareness in dementia: Heterogeneity and its implications[END_REF][START_REF] Jacus | Awareness, apathy and depression in Alzheimer's disease and mild cognitive impairment[END_REF]. Recent research found negative correlations with depression and positive associations with apathy. These associations were observed using the patient-caregiver discrepancy method [START_REF] Jacus | Awareness, apathy and depression in Alzheimer's disease and mild cognitive impairment[END_REF]. Other associations, particularly with executive functions, were observed using the prediction of performance discrepancy method [START_REF] Antoine | Awareness of deficits in Alzheimer's disease patients: Analysis of performance prediction discrepancies[END_REF]. However, many awareness studies have produced contrasted results due to these different methodologies or different stages of the disease [START_REF] Avondino | Heterogeneity of Cognitive Anosognosia and its Variation with the Severity of Dementia in Patients with Alzheimer's Disease[END_REF][START_REF] Horning | Insight in Alzheimer's disease and its relation to psychiatric and behavioral disturbances[END_REF][START_REF] Marková | Phenomena of awareness in dementia: Heterogeneity and its implications[END_REF]. Furthermore, these studies frequently used stepwise regression analyses, which are more suited to providing predictors of a phenomenon than to reflecting relationships between the phenomenon (for instance awareness) and risk factors (e.g. the stage of AD), so as to model that phenomenon. Indeed stepwise regression analyses do not consider confounding factors.

Confounders are not significant factors, but their removal impacts the exposure factor estimate without interacting with it. Thus, removing a confounding variable can bias the risk factor coefficient estimate. A multivariate analysis using an exposure (risk) factor appears as better suited to modeling the relationship between awareness and the exposure factor if the different factors involved in the phenomenon (apathy, depression, executive functions, etc.) are tested as potential confounders [START_REF] Alioum | DU Méthodes statistiques de régression en épidémiologie, 2015-2016: Méthodes de régression linéaire simple et multiple[END_REF][START_REF] Heinze | Variable selection -A review and recommendations for the practicing statistician[END_REF].

Our study aimed to investigate the relationship between awareness and AD severity, taking into account different approaches to awareness. We hypothesized that apathy and depression would be significantly involved across the different approaches, whereas confounding factors would be more specific to a single approach or assessment method.

Materials and method Participants

Eighty-six -86 participants took part in the study. Twenty-five -25 were Healthy Controls (HC) recruited from a pool of participants and senior-citizen associations. They had no memory complaint and scored normally on a background assessment using the Mini Mental State Examination -MMSE [START_REF] Folstein | Mini Mental State. A practical method for grading the cognitive state of patients for the clinician[END_REF][START_REF] Lechevallier-Michel | Normative data for the MMSE, the Benton visual retention test, the Isaacs's set test, the digit symbol substitution test and the Zazzo's cancellation task in subjects over the age 70: results from the PAQUID Study[END_REF], the Free and Cued Recall test -FCRT [START_REF] Ergis | L'exploration des troubles de la mémoire épisodique dans la maladie d'Alzheimer débutante au moyen d'une épreuve de rappel indicé[END_REF][START_REF] Van Der Linden | Présentation de quatre tests de mémoire épisodique (avec leur étalonnage): L'épreuve de rappel libre/rappel indicé à 16 items (RL/RI-16)[END_REF], the Delayed Match to Sample test [START_REF] Barbeau | Evaluation de la mémoire de reconnaissance visuelle: normalisation d'une nouvelle épreuve en choix forcé (DMS 48) et utilité en neuropsychologie clinique[END_REF] and the Frontal Assessment Battery -FAB [START_REF] Dubois | The FAB: A frontal assessment battery at bedside[END_REF]. Sixty-one -61 participants were patients recruited from a memory center. They were diagnosed by a senior neurologist and a neuropsychologist (JP. J) for probable AD according to the recommendations of the National Institute on Aging and the Alzheimer's Association working group on diagnostic guidelines for AD [START_REF] Mckhann | The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging and the Alzheimer's Association workgroup on diagnostic guidelines for Alzheimer's disease[END_REF]. The stage of the disease was determined using the MMSE score (mild to moderately severe) [START_REF] Hugonot-Diener | The Mini Mental Status Examination or MMSE consensual version of GRECO[END_REF]. All participants signed consent to participate and this study was approved by the local ethics committee.

Evaluation tools Additional factor assessments

We assessed three additional factors usually involved in awareness: (1) Depression with the Geriatric Depression Scale [START_REF] Clément | Development and contribution to the validation of a brief French version of the Yesavage Geriatric Depression Scale[END_REF] (GDS) -the higher the score, the higher the level of depression ; (2) Apathy with the Apathy Evaluation Scales [START_REF] Marin | Reliability and validity of the apathy evaluation scale[END_REF] (scored by a relative: AES Relative and the clinician: AES Clinician ) -higher scores indicate lesser apathy -and (3) Autonomy with the Instrumental Activity of Daily Living scale (IADL) scored by a relative [START_REF] Lawton | Assessment of older people: self-maintaining and instrumental activities of daily living[END_REF] -the greater the autonomy, the higher the score.

Awareness assessments

As indicated above, four measures derived from the three assessment methods were used to assess awareness.

Concerning patient-caregiver discrepancy, we used (1) the Patient Competency Rating Scale

-PCRS [START_REF] Prigatano | Cognitive dysfunction and psycho-social adjustment after brain injury[END_REF] and (2) the Anosognosia Questionnaire for Dementia -A-QD [START_REF] Starkstein | A diagnostic formulation for anosognosia in Alzheimer's disease[END_REF]. [START_REF] Starkstein | Anosognosia in Alzheimer's disease: Diagnosis, frequency, mechanism and clinical correlates[END_REF] The PCRS requires the participant and a relative to answer the same 30 questions on the participant's ability to perform various tasks of daily living, with particular reference to emotional control.

The level of awareness is assessed by subtracting the participant rating from the relative rating. A negative score indicates poorer awareness. (2) The A-QD is based on the same principle as the PCRS, but mainly concerns memory and behavioral disturbances in AD. A positive score indicates poorer awareness.

Concerning the prediction of performance discrepancy, we used the Multidimensional Isomorphic Simple Awareness Assessment -MISAware [START_REF] Antoine | Awareness of deficits in Alzheimer's disease patients: Analysis of performance prediction discrepancies[END_REF]. Here, the participant is asked to predict his(her) neuropsychological performance (correct / incorrect) on the Dementia obtained. The poorer the awareness the higher the score.

Finally concerning the clinical rating, the Self-Consciousness Scale in AD -SCSAD -was used only with patients because inappropriate for HC [START_REF] Jacus | Awareness, apathy and depression in Alzheimer's disease and mild cognitive impairment[END_REF][START_REF] Gil | Selfconsciousness and Alzheimer's disease[END_REF]. The SCSAD is a structured patient interview including fourteen questions in seven domains: identity, knowledge of cognitive disturbances, affective state, bodily representation, prospective memory, introspection abilities, and moral judgments. The better the awareness the higher the score.

Statistical analyses

The statistical analyses were carried out using R software (version 3.6.1.) with the Hmisc package. As the HC group comprised fewer than 30 subjects, approximation with a Gaussian distribution was not possible and non-parametric tests were used to compare the performances between HC and patients.

A multivariate regression analysis was performed on the patient group (n=61). We performed a backward manual regression for each of the four global measures of awareness, using the following variable selection method [START_REF] Alioum | DU Méthodes statistiques de régression en épidémiologie, 2015-2016: Méthodes de régression linéaire simple et multiple[END_REF][START_REF] Heinze | Variable selection -A review and recommendations for the practicing statistician[END_REF]:

The MMSE score was used as the exposure factor determining the stage of AD [START_REF] Heinze | Variable selection -A review and recommendations for the practicing statistician[END_REF] and was maintained in the model even if it was non-significant. Demographics (age, educational level in years, gender), autonomy (IADL), executive functioning (FAB), apathy (AES) and depression (GDS) were univariately tested with each of the four global measures of awareness (dependent variable). The cut-off was set at p<0.25 for this preliminary model to avoid excluding future significant variables. Each interaction between the exposure factor (MMSE) and the variables retained in the preliminary model was univariately tested with the dependent variable. The cut-off was set at p<0.05. Once the preliminary model was established with the selected interactions, the backward process began, removing one by one the non-significant interactions (p<0.05), beginning with those having the highest pvalues. The same process was performed with the non-significant main factors (p<0.05).

When removal impacted at least 15% of the exposure factor estimate (relative variation), the factor was considered as a potential confounder and was therefore maintained in the model, knowing that this relative variation is significant as it falls between 10 to 20% [START_REF] Alioum | DU Méthodes statistiques de régression en épidémiologie, 2015-2016: Méthodes de régression linéaire simple et multiple[END_REF]. The analysis was discontinued when there were no remaining significant factors. Confounding factors and the exposure factor (MMSE) remained in the final model. Finally, we ascertained that confounding variables were not effect-modifiers by testing their interactions with the exposure factor (p<0.05).

Results

Comparisons between HC and patients

HC were younger (W=275.5, p<0.0001) and more educated than patients (W=1127.5, p=0.0005). The groups were matched for gender (χ²=0.0396, p=0.8422). HC performed better than patients for all cognitive variables including autonomy (MMSE, FAB and IADL: p<0.0001). They were less apathetic (AES Relative and AES Clinician : p<0.0001) and less depressed than patients (W=545, p=0.0368).

Concerning awareness, patient-caregiver discrepancy data showed a significant group effect on the PCRS (W=1157, p<0.0002 [HC>AD]), and on the A-QD (W=382, p=0.0003 [HC<AD]).

Concerning prediction of performance discrepancy, the MISAware data showed a significant group effect (W=61, p<0.0001, [HC<AD]). Thus HC were more aware than patients on all the awareness scales (Table 1).

On the whole sample, and in the patients group, all the awareness scales correlated one to another, except the SCSAD with the PCRS (p=0.0564) and with the A-QD (p=0.0719) (the pvalues are the same because the SCSAD was used only with the patient group).

On the whole sample, and in the patients group, all the variables (age, educational level, MMSE, BREF, IADL, AES Relative , AES Clinician ), correlated one to another (p<0.01 because of the number of variables), except for depression (GDS) which did not correlate with any other.

Regression analyses

Using the exposure factor (MMSE), demographic data (age, educational level, gender), and the available variables (IADL, FAB, GDS, AES Relative and AES Clinician ), we ran four models with the patient group only (one for each awareness scale used), because of differences in awareness between the groups and in order to model awareness in AD (Table 2).

The first model involving the PCRS comprised the MMSE, IADL, GDS, AES Relative and gender.

Here the PCRS score was mainly explained by the GDS score (β=3.71, p<0.0001) and the AES Relative score (β=0.89, p=0.0002). The IADL score (β=2.13) and the gender (β=-6.56) were confounding factors and non-significant (p>0.05). The exposure factor (MMSE: β=-1.09) was non-significant (p>0.05).

The second model involving the A-QD included the MMSE, IADL, GDS and AES Relative scores.

Here the A-QD score was mainly explained by the GDS score (β=-2.36, p=0.0001) and the AES Relative score (β=-0.61, p=0.0001). The IADL score (β=-1.31) was confounding factor and non-significant (p>0.05). The exposure factor (MMSE: β=0.45) was non-significant (p>0.05).

The third model involving the SCSAD included the MMSE, FAB, GDS, AES Relative and AES Clinician scores. Here the SCSAD was mainly explained by the GDS score (β=0.28, p=0.0022) and the AES Clinician score (β=0.09, p=0.0168). The FAB (β=0.09) and the AES Relative scores (β=0.04) were confounding factors and non-significant (p>0.05). The exposure factor (MMSE: β=0.01) was not significant (p>0.05).

The fourth model involving the MISAware comprised the MMSE, IADL, FAB, and AES Relative scores. Here the MISAware was mainly explained by the MMSE (β=-0.53, p=0.0178), the FAB (β=-1.24, p<0.0001) and the AES Relative scores (β=-0.17, p=0.0325). The IADL score (β=1.06) was confounding factor and non-significant (p>0.05).

None of the confounding variables were effect modifiers in any model. For all models, residuals analyses showed normal fit: Shapiro test for the PCRS: W=0.9711, p=0.1578; for the A-QD: W=0.9761, p=0.2766; for the SCSAD: W=0.9647, p=0.0757; and for the MISAware: W=0.9691, p=0.126. Linearity and homoscedasticity were satisfactory:

Snedecor test for the PCRS: =0.8857, p=0.6399; for the A-QD: =0.8267, p=0.4633); for the SCSAD: =0.6435, p=0.0904; and for the MISAware: =0.9165, p=0.7367 (Figure 1).

Discussion

These results suggest that apathy and depression are significantly linked to awareness as measured in the different approaches, whatever the stage of the disease. Horning et al. [START_REF] Horning | Insight in Alzheimer's disease and its relation to psychiatric and behavioral disturbances[END_REF] reported that more intact insight was related to anxiety and depressed mood, whereas impaired insight was related to greater apathy, after adjusting their regression analyses on the MMSE. Our results show that this can be considered as independent from the assessment method. Nevertheless, our hypotheses are not totally validated. Firstly, perfect homogeneity of awareness cannot be argued from these results because one assessment method (MISAware) was not mainly explained by depression but by cognitive factors and apathy. Secondly, the confounders were globally similar across approaches and no factors specific to each awareness approach were found. Thus, our results show homogeneity overall, but certain heterogeneities in awareness measures in AD.

Our results could suggest that the nature of the factors found to be associated (affective and behavioral or cognitive) depends on the referential used to assess awareness (human or test rating). Thus, It is likely that different awareness phenomena are captured according to the referential used [START_REF] Marková | Phenomena of awareness in dementia: Heterogeneity and its implications[END_REF]. Thus in clinical practice, choosing an awareness measure should be based more on practical aspects than on anything else, each method being here sensitive to AD. Although considered to be more reliable [START_REF] Starkstein | Anosognosia in Alzheimer's disease: Diagnosis, frequency, mechanism and clinical correlates[END_REF][START_REF] Ryu | Self-and informant-reported cognitive functioning and awareness in subjective cognitive decline, mild cognitive impairment, and very mild Alzheimer disease[END_REF], the patient-caregiver discrepancy method appears difficult to use in the moderate stages of AD (several response formats, items addressed to patients living at home, etc.), whereas prediction of performance discrepancy (using a dementia scale) and the clinical rating methods seem more suited to this.

Preventive action could also be undertaken on depression and on apathy to maintain awareness of deficits as comfortably as possible for the patients, since its impairment can result in a loss of autonomy, widely contribute to the caregiver's burden and finally lead to early placement in a structured living environment [START_REF] Horning | Insight in Alzheimer's disease and its relation to psychiatric and behavioral disturbances[END_REF][START_REF] Marková | Phenomena of awareness in dementia: Heterogeneity and its implications[END_REF][START_REF] Jacus | Awareness, apathy and depression in Alzheimer's disease and mild cognitive impairment[END_REF].

Several limitations should however be underlined. Patients and HC were not matched for group size and the patient sample size could be criticised in relation to our statistical strategy derived from epidemiological methods. There was collinearity between the factors

Table 1 :

 1 Demographic, cognitive, behavioral and awareness data across the groups * Mann & Whitney test ; **Chi squared test. Exposure factor (maintained even if it was not significant); b Confounding factors (when removal impacted at least 15% of the exposure factor estimate, therefore kept in the model although not significant); Significant variables.Figure 1: Plots of normality and homoscedasticity for each model

			HC (n=25)	Patients (n=61)
		Variables			Statistics	p
			Med. (min;max)	Med. (min;max)
		Age (years)	73 (61;85)	82 (62;92)	W=275.5* <0.0001 a
	Demographic	Education (years) Gender (% female)	14 (8;20) 56.00	10 (6;18) 50.8 ²=0.0396** W=1127.5*	0.0005 b 0.8422
		IADL	8 (8;8)	6 (3;8)	W=1400* <0.0001 a
	Cognitive	MMSE BREF	29 (26;30) 17 (15;18)	23 (13;28) 13 (6;18)	W=1485* <0.0001 a W=1345.5* <0.0001 a
	/ mood Behavioral	GDS AES relative AES clinician	3 (0;10) 64 (43;72) 67 (53;72)	4 (0;11) 45 (25;68) 49 (33;67)	W=545* W=1359* <0.0001 b 0.0368 b W=1478* <0.0001 b
		PCRS	2 (-17;22)	-12(-55;45)	W=1157*	0.0002 b
	Awareness	AQ-D MISAware	-5 (-19;10) 0 (0;4)	5 (-23;37) 9 (0;35)	W=382* W=61* <0.0001 a 0.0003 a
		Self Consciousness	---	23 (20;27)	---	---

a HC<AD ; b HC>AD a

entered into the model, and the model did not reflect all the variables known to be involved in awareness. Nevertheless, all models complied with the validity conditions for linear models. Additional research on awareness in AD is required to confirm this and explore a possible depression-apathy continuum, using longitudinal methodologies.

The authors have no conflict of interest to report.

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Julien Thierry

Sophie Herpin

Fabrice Rodriguez

Marie Gantois

Pierre-Emmanuel Bournet

ICUC 2023_A&C Projet CoolTrHyd

The multiplication and intensification of heatwaves due to climate change increases human thermal stress during summertime, especially in cities where urban configuration and materials enhance overheating. Street trees may lower the thermal stress of pedestrians with two main benefits: cast shadows and evapotranspiration. However, climate change is also accompanied with an increase in evaporative demand and frequency of dry periods. Street trees are thus facing water restriction, which may impact their physiology, development and thereby their climatic benefits.

With the aim of understanding the climatic benefits and behaviour of various species of trees during heatwaves and droughts, the green spaces department of the City of Paris started in 2018 the "Trees and Climate" in-situ study. 36 street trees representing 9 species and located in 5 sites in Paris, were equipped with meteorological sensors aiming at assessing the Universal Thermal Climate Index inside and outside the tree crowns. The physiological response of the trees was monitored through the branch diameter micro-variation measurement. Water availability was also measured in the tree pits and other morphological variables such as the crown density were measured using terrestrial LiDAR. Field surveys were conducted with a one-hour time-step from May 2019 to September 2022.

In summer, several trees experienced branch diameter shrinkage as their water availability was decreasing (figure 1), meaning they probably used water contained in their tissues to keep transpiration running. Nevertheless, important human thermal stress reductions were measured inside the tree crowns of all species, even during heatwaves and droughts (figure 2). Further works will try to assess the relative influence of water availability, meteorological conditions and morphological variables on the variability of the benefits over time and between species. This study is expected to help stakeholders select the most adapted species regarding the resistance to drought and the microclimate mitigation in Paris.

Figure 1 :

 1 Figure1: Evolution of the water matric potential (the higher the water potential, the lower the water availability for the tree) and the branch diameter variation for one studied Sophora japonica and one studied Celtis australis during summer 2020.

Figure 2 :

 2 Figure 2: Evolution of the Universal Thermal Climate Index (UTCI) calculated on a reference point outside the tree crowns and inside the crown of one studied Sophora japonica and one studied Celtis australis on August 9, 2020 during a heatwave.