Low Cognitive Awareness, but Not Complaint, is a Good Marker of Preclinical Alzheimer's Disease

Subjective cognitive decline (SCD) may result from many conditions, including Alzheimer's disease (AD)

Positive symptoms of episodic memory in Alzheimer’s disease, from preclinical to dementia stages

La Maladie d’Alzheimer (MA) est une pathologie neurodégénérative définie par la combinaison d’un syndrome comportemental progressif et de lésions cérébrales spécifiques. Au cours des dernières décennies, de nombreux essais thérapeutiques furent entrepris. Néanmoins, si certains traitements permettent aujourd’hui d’agir sur la quantité de lésions ou encore de ralentir l’évolution cognitive, aucun traitement curatif n’a encore été mis au point. L’une des principales hypothèses de ces échecs est chronologique, les chercheurs postulant que les traitements seraient délivrés trop tard, à un instant où cette dernière aurait déjà causé des dommages biologiques irréversibles. Ainsi, un nombre important de recherches s’oriente actuellement vers la description des stades précliniques de la MA, avec notamment l’idée de déterminer les indices (tant comportementaux que biologiques) qui pour- raient permettre de prédire un diagnostic ultérieur. Dans cette optique, au cours de ce travail, nous tentons d’établir des mesures cognitives permettant de décrire au mieux cette étape précoce de l’évolution de la MA. Nous nous focalisons plus particulièrement sur la sphère mnésique, cette dernière étant particulièrement im- pliquée dans le phénotype de la MA. Une première partie de ce travail porte sur la MA post-diagnostic, mettant notamment en évidence la présence de liens entre les erreurs mnésiques et des aspects cognitifs et biologiques. Dans une seconde partie, nous démontrons que ces mêmes relations sont présentes à un stade préclinique de la pathologie, lorsque les patients présentent un déclin cognitif subtil. Pour finir, notre travail met en évidence un lien entre l’atteinte biologique caractéristique de la MA et un défaut de conscience de troubles mnésiques.Alzheimer’s Disease (AD) is a neurodegenerative pathology defined by the com- bination of progressive behavioral syndrome and specific brain damage. In recent decades, many therapeutic trials have been undertaken. Although some treatments can reduce the number of lesions or slow down cognitive development, no curative treatment has yet been developed. One of the main hypotheses of these failures is that treatments would be delivered too late, at a time when they would already have caused irreversible biological damage. Thus, a significant amount of research currently focuses on describing the preclinical stages of AD and determining the indicators (both behavioral and biological) that could predict a subsequent diagnosis. In this work, we try to establish cognitive measures that best describe this early stage in the evolution of AD. We focus particularly on memory, which is particularly involved in the phenotype of AD. A first part of this work focuses on post-diagnosis AD, highlighting the presence of links between memory errors and cognitive and biological aspects. In the second part, we demonstrate that these same relationships are present at a preclinical stage of the pathology, when patients present a subtle cognitive decline. Finally, our work highlights a link between the biological damage characteristic of AD and a lack of awareness of memory disorders

Troubles positifs de la mémoire épisodique dans la maladie d'Alzheimer, du stade préclinique à la démence

Alzheimer’s Disease (AD) is a neurodegenerative pathology defined by the com- bination of progressive behavioral syndrome and specific brain damage. In recent decades, many therapeutic trials have been undertaken. Although some treatments can reduce the number of lesions or slow down cognitive development, no curative treatment has yet been developed. One of the main hypotheses of these failures is that treatments would be delivered too late, at a time when they would already have caused irreversible biological damage. Thus, a significant amount of research currently focuses on describing the preclinical stages of AD and determining the indicators (both behavioral and biological) that could predict a subsequent diagnosis. In this work, we try to establish cognitive measures that best describe this early stage in the evolution of AD. We focus particularly on memory, which is particularly involved in the phenotype of AD. A first part of this work focuses on post-diagnosis AD, highlighting the presence of links between memory errors and cognitive and biological aspects. In the second part, we demonstrate that these same relationships are present at a preclinical stage of the pathology, when patients present a subtle cognitive decline. Finally, our work highlights a link between the biological damage characteristic of AD and a lack of awareness of memory disorders.La Maladie d’Alzheimer (MA) est une pathologie neurodégénérative définie par la combinaison d’un syndrome comportemental progressif et de lésions cérébrales spécifiques. Au cours des dernières décennies, de nombreux essais thérapeutiques furent entrepris. Néanmoins, si certains traitements permettent aujourd’hui d’agir sur la quantité de lésions ou encore de ralentir l’évolution cognitive, aucun traitement curatif n’a encore été mis au point. L’une des principales hypothèses de ces échecs est chronologique, les chercheurs postulant que les traitements seraient délivrés trop tard, à un instant où cette dernière aurait déjà causé des dommages biologiques irréversibles. Ainsi, un nombre important de recherches s’oriente actuellement vers la description des stades précliniques de la MA, avec notamment l’idée de déterminer les indices (tant comportementaux que biologiques) qui pour- raient permettre de prédire un diagnostic ultérieur. Dans cette optique, au cours de ce travail, nous tentons d’établir des mesures cognitives permettant de décrire au mieux cette étape précoce de l’évolution de la MA. Nous nous focalisons plus particulièrement sur la sphère mnésique, cette dernière étant particulièrement im- pliquée dans le phénotype de la MA. Une première partie de ce travail porte sur la MA post-diagnostic, mettant notamment en évidence la présence de liens entre les erreurs mnésiques et des aspects cognitifs et biologiques. Dans une seconde partie, nous démontrons que ces mêmes relations sont présentes à un stade préclinique de la pathologie, lorsque les patients présentent un déclin cognitif subtil. Pour finir, notre travail met en évidence un lien entre l’atteinte biologique caractéristique de la MA et un défaut de conscience de troubles mnésiques

The meta-memory ratio: a new cohort- independent way to measure cognitive awareness in asymptomatic individuals at risk for Alzheimer's disease

International audienceBackground: Lack of awareness of cognitive decline (ACD) has been described at the preclinical and prodromal stages of Alzheimer's disease (AD). In this study, we introduced a meta-memory ratio (MMR) and explored how it is associated with neuroimaging AD biomarkers in asymptomatic individuals at risk for AD. Method: Four hundred forty-eight cognitively healthy participants from two cohorts of subjective memory complainers (INSIGHT-PreAD and ADNI) were included. Regression models were used to assess the impact of AD biomarkers on the MMR. Result: In both cohorts, there was a significant quadratic effect of cerebral amyloidosis on the MMR value. In particular, participants had a high ACD up to the amyloid positivity threshold, above which a decrease of ACD was eventually observed as the amyloid load increased. Conclusion: This nonlinear evolution of ACD in very early AD must be taken into account in clinical care and for trial enrollment as well

Pathological correlates of impaired self-awareness of memory function in Alzheimer's disease.

Impaired self-awareness of memory function, a.k.a. anosognosia, is a common symptom in Alzheimer's disease (AD); however, its pathological correlates remain unclear. Here, we investigated the impact of amyloid and tau on memory self-awareness. Two hundred thirty-six clinically normal (N) and 102 impaired (I) participants from the ADNI cohort were included. Amyloid (global) and tau burden (in entorhinal and inferior temporal cortices) were assessed using positron emission tomography (PET). Self-awareness of memory was assessed using discrepancy indexes of subjective participant-informant ratings, as well as participant-objective scores of memory performance. Subjective and objective values were derived from the Everyday Cognition memory questionnaire and Logical Memory (delayed recall). Lower awareness (both methods) of memory function was associated with higher levels of pathology in the I group as compared to N. There was a significant effect of tauopathy, but not amyloidosis, on individual complaint, such that higher levels of tau associated with lower awareness. Impaired self-awareness appears progressively in the evolution of the disease related to AD biomarkers. Discordant subjective and objective measures may be important for clinical consideration

Reduction of recruitment costs in preclinical AD trials. Validation of automatic pre-screening algorithm for brain amyloidosis

International audienceWe propose a method for recruiting asymptomatic Amyloid positive individuals in clinical trials, using a two-step process. We first select during a pre-screening phase a subset of individuals which are more likely to be amyloid positive based on the automatic analysis of data acquired during routine clinical practice, before doing a confirmatory PET-scan to these selected individuals only. This method leads to an increased number of recruitments and to a reduced number of PET-scans, resulting in a decrease in overall recruitment costs. We validate our method on 3 different cohorts, and consider 5 different classification algorithms for the pre-screening phase. We show that the best results are obtained using solely cognitive, genetic and socio-demographic features, as the slight increased performance when using MRI or longitudinal data is balanced by the cost increase they induce. We show that the proposed method generalizes well when tested on an independent cohort, and that the characteristics of the selected set of individuals are identical to the characteristics of a population selected in a standard way. The proposed approach shows how Machine Learning can be used effectively in practice to optimize recruitment costs in clinical trials

Prediction of amyloidosis from neuropsychological and MRI data for cost effective inclusion of pre-symptomatic subjects in clinical trials

International audienceWe propose a method for selecting pre-symptomatic subjects likely to have amyloid plaques in the brain, based on the automatic analysis of neuropsychological and MRI data and using a cross-validated binary classifier. By avoiding systematic PET scan for selecting subjects, it reduces the cost of forming cohorts of subjects with amyloid plaques for clinical trials, by scanning fewer subjects but increasing the number of recruitments. We validate our method on three cohorts of subjects at different disease stages, and compare the performance of six classifiers, showing that the random forest yields good results more consistently, and that the method generalizes well when tested on an unseen data set

Validation francophone du Toddler Attention Questionnaire, un questionnaire d'attention des jeunes enfants

Objectives: There is a lack of tools for non-parental caregivers and in the French language to assess the quality of the attachment relationship with toddlers. The Toddler Attention Questionnaire (TAQ) is an Italian scale created for caregivers in day care centers. By its focus on the exploration system, the TAQ offers the opportunity to study the relation between attention characteristics and attachment behavior in toddlers. In the attachment theory, a link is often assumed between these two concepts. Mary Main has described the different attachment patterns (secure, insecure avoidant, insecure ambivalent-resistant, disorganized) by using cognitive psychology dimensions relying on attentional processes. However, this relation is hardly proven scientifically and study results in this field are not always congruent. The validation of the TAQ in French, main purpose of this study, is likely to add new contributions to this field. Materials and methods: The Toddler Attention Questionnaire is composed of 29 self-reported items and four dimensions which describe 4 attentional processes: lability, flexibility, detachment, disorientation. The items present different behaviors and measure, on a five-point Likert scale, the quality of children's attention during exploration. The French translation was made by two native bilingual persons following the back translation procedure and was administered to the primary caregiver, who was in charge of each child in 13 French daycare centers. The questionnaires were completed for 148 children aged from 20 to 36 months who attended to the daycare center at least 20 hours per week. Results: The analyses show a robust structure into three dimensions: the disorientation subscale was deleted because of its reduced contribution to the total variance. Some items were also shifted (9 items) or deleted (6 items) compared to their contribution to the different dimensions. Moreover, a qualitative analysis of the remarks from the participants allowed to adapt some items' formulation (4 items). The final French version of the TAQ, composed of 23 items, explained 46.94 % of the variance. The Cronbach's Alphas ranged from 0.64 (Flexibility) to 0.83 (Lability). The TAQ is a dimensional tool: the sum of the scores gives a position of the child behavior in a continuum of attachment security in each dimension. Conclusions: Two main differences between the present validation and the original study may limit generalization and comparability. First, we adopted large selection criteria, including children who attended to a daycare center at least 20 hours per week, instead of 36 hours per week of the original study. This choice allowed to collect more questionnaires and to be closer to the total rate of hours attended by French children in daycare center. Second, our sample of professional participants was more heterogeneous than the Italian sample regarding the professional experiences and the seniority in the daycare center. With few items, well-defined questions and easy administration, the TAQ seems to be a cost-effective alternative to the traditional methods used to assess attachment behaviors such as the Strange Situation or the Attachment Q-Sort. Hence, the major advantage of our validation is to allow French researchers to carry out studies with large samples in the attachment field, particularly with toddlers and professional caregivers. Studying the secondary attachment relationship is essential to highlight how a child copes with the absence of his primary attachment figure in the daycare center. Moreover, the focus on attention processes is important to prevent attention deficits and learning difficulties and to reduce its potential effect on the child's development. Nevertheless, further research would be needed to extend its psychometric proprieties (convergent, discriminant and test-retest validity) and to examine its clinical usefulness

Low Cognitive Awareness, but Not Complaint, is a Good Marker of Preclinical Alzheimer's Disease.

International audienceBackground:Subjective cognitive decline (SCD) may result from many conditions, including Alzheimer’s disease (AD). Objective:In this study, we searched for a specific pattern of SCD in asymptomatic individuals at risk for AD. Methods:Cognitively normal older adults (N = 318) reporting SCD and their informants were enrolled in the INSIGHT-PreAD cohort. We examined the relationship between six SCD measures and both cognitive scores and AD neuroimaging markers (amyloid burden, hippocampal atrophy and brain hypometabolism). An awareness of cognitive decline index (ACDI) has been introduced based on the subject-informant discrepancy in a questionnaire of SCD and participants with low versus high awareness were compared. Results:Scores in the INSIGHT-PreAD SCD questionnaires did not correlate with AD neuroimaging markers. As well, no correlation has been found between SCD measures and cognitive scores. Comparing subjects with a low (n = 19) and high (n = 86) level of awareness, no significant difference in terms of demography, neuropsychiatric symptoms, autonomy, quality of life, cognition, and hippocampal volume was found. However, the “low awareness” group showed greater amyloid burden and lower cortical metabolism, compared to the “high awareness” group. Conclusion:This study provided additional evidence that reporting SCD by itself is not a specific symptom of preclinical AD. Conversely, a low cognitive awareness (namely, when subjects report fewer difficulties than their relatives do) may represent a very early form of anosognosia and serve as a specific indicator of preclinical AD. This finding is of key importance as an enrichment factor to consider in both clinical practice and research trials

Anosognosia is associated with increased prevalence and faster development of neuropsychiatric symptoms in mild cognitive impairment

International audienceINTRODUCTION: Both the loss of awareness for cognitive decline (a. k.a anosognosia) and neuropsychiatric symptoms (NPS) are common in patients with Alzheimer's disease (AD) dementia, even in prodromal stages, and may exacerbate functional impairment and negatively impact caregiver burden. Despite the high impact of these symptoms on patients and their caregivers, our knowledge of how they develop across the AD spectrum is limited. Here, we explored the cross-sectional and longitudinal associations between anosognosia and NPS in individuals with mild cognitive impairment (MCI). METHODS: We included 237 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) with a baseline clinical diagnosis of MCI. Everyday Cognition (ECog) questionnaire scores were used to measure complaints from participants and study-partners at baseline and annually over a mean of 4.29 years [standard deviation (SD) = 2.72]. Anosognosia was defined as the study-partner having an ECog score ≥2.5/4 and the participant having an ECog score 0.9), though participants with anosognosia had lower MMSE scores (p = 0.049) and a higher proportion of amyloid-positivity using PET (p < 0.001. At baseline, the frequencies of agitation (p = 0.029) and disinhibition (p < 0.001) were higher in the anosognosia group compared to the non-anosognosia group. Survival analyses showed earlier onset of seven of the 12 NPS in the anosognosia group (p's < 0.001). DISCUSSION: Loss of awareness for cognitive decline is associated with greater frequency and earlier onset of NPS over time in participants with MCI. These results support the hypothesis of a potential common underlying neurophysiological process for anosognosia and NPS, a finding that needs to be addressed in future studies