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

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

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

Awareness of Cognitive Decline in Patients With Alzheimer's Disease: A Systematic Review and Meta-Analysis

International audienceBackground: Identifying a poor degree of awareness of cognitive decline (ACD) could represent an early indicator of Alzheimer's disease (AD). Objectives: (1) to understand whether there is evidence of poor ACD in the pre-dementia stages of AD; (2) to summarize the main findings obtained investigating ACD in AD; (3) to propose a conceptual framework. Conclusions and Implications: We propose that patients may be complaining of their initial subtle cognitive changes, but ACD would soon start to decrease. The individual would show mild anosognosia in the MCI stage, and severe anosognosia in dementia. The evaluation of ACD (comparing self-report to cognitive scores or to informant-report) could be useful to guide the clinician toward a timely diagnosis, and in trials targeting early-stage AD

Suspected non-alzheimer disease pathophysiology (SNAP) categorization in the insight cohort

BackgroundSuspected non-Alzheimer disease pathophysiology (SNAP) individuals are participants to studies on Alzheimer’s disease (AD) biomarkers that are considered positive for markers of neurodegeneration and negative for markers of brain amyloidosis in the absence of a major neurocognitive disorder. This concept probably encompasses numerous neurological diseases in which the mildness of symptoms is responsible for a generic term to be proposed instead of a diagnosis.MethodsWe categorized SNAP subjects in the INSIGHT cohort, a mono-centric French cohort at the University Salpêtrière Hospital in Paris including 317 individuals with subjective cognitive decline (SCD) between 70-85 year. Standardized demographic, cognitive, MRI, 18FDG and AV45 PET imaging were performed in each subject. The SNAP population was determined based on cut-offs scores adapted from the literature. Each SNAP participant’s complete medical file was analyzed by an expert committee comprised of 3 neurologists, 1 geriatrician, 1 neuropsychologist, 1 neuroradiologist and 1 nuclear medicine MD. Diagnostic algorithms were adapted from international consensus criteria for various neurological conditions (eg Rascovsky’s criteria for Fronto-temporal dementia).ResultsAmong the INSIGHT participants, 88 are considered amyloid (+) with a significantly increased cortical uptake of the tracer above threshold on PET imaging, and 229 are amyloid (-). The 229 amyloid negative individuals were categorized in 4 groups determined by their clinico-radiological status: Healthy control, SNAP-AD when neurodegeneration was suggestive of AD, SNAP-NONAD when the neurodegeneration was incompatible with typical AD and SNAP-MIXED in all other participants. We have then applied our diagnostic procedure in the SNAP participants to determine if this group can be divided into known neurological diseases.ConclusionsThis is one of the first attempts to refine the diagnostic procedure in SNAP, a frequent condition in the elderly population. Similarly to AD, a presymptomatic/early symptomatic phase of different brain affections can be diagnosed instead of using the SNAP acronym

Which Episodic Memory Performance is Associated with Alzheimer's Disease Biomarkers in Elderly Cognitive Complainers? Evidence from a Longitudinal Observational Study with Four Episodic Memory Tests (Insight-PreAD)

Alzheimer's disease (AD) pathology is found in the brain years before symptoms are usually detected. An episodic memory (EM) decline is considered to be the specific cognitive sign indicating a transition from the preclinical to the prodromal stage of AD. However, there is still no consensus on the most sensitive tool to detect it

Preclinical Alzheimer's disease: a systematic review of the cohorts underlying the concept

International audiencePreclinical Alzheimer's disease (AD) is a relatively recent concept describing an entity characterized by the presence of a pathophysiological biomarker signature characteristic for AD in the absence of specific clinical symptoms. There is rising interest in the scientific community to define such an early target population mainly due to failures of all recent clinical trials despite evidence of biological effects on brain amyloidosis for some compounds. A conceptual framework has recently been proposed for this preclinical phase of AD. However, few data exist on this silent stage of AD. We performed a systematic review in order to investigate how the concept is defined across studies. The review highlights the substantial heterogeneity concerning the three main determinants of preclinical AD: " normal cognition " , " cognitive decline " and " AD pathophysiological signature ". We emphasize the need for a harmonized nomenclature of the preclinical AD concept and standardized population-based and case-control studies using unified operationalized criteria