Cognitive Function and Amyloid Marker in Frail Older Adults: The COGFRAIL Cohort Study.

BACKGROUND: Frailty and cognitive impairment are common manifestations of the ageing process and are closely related. But the mechanisms linking aging, physical frailty, and cognitive disorders, are complex and remain unclear. OBJECTIVES: We aim to explore the role of cerebral amyloid pathology, but also a range of nutritional, physical, biological or brain-aging marker in the development of cognitive frailty. METHOD: COGFRAIL study is a monocentric prospective study of frail older patients with an objective cognitive impairment (Clinical Dementia Rating Scale global score at 0.5 or 1). Three-hundred-and-twenty-one patients are followed up every 6 months, for 2 years. Clinical assessment at baseline and during follow-up included frailty, physical, mood, sensory, nutritional, and cognitive assessment (with a set of neuropsychological tests). Cerebral amyloid pathology is measured by amyloid Positron Emission Tomography (PET) or amyloid-ß-1-42 level in cerebrospinal fluid. Brain magnetic resonance imaging, measurement of body composition using Dual X Ray Absorptiometry and blood sampling are performed. The main outcome of the study is to assess the prevalence of positive cerebral amyloid status according to amyloid PET or amyloid-ß-1-42 level CSF. Secondary outcomes included biological, nutritional, MRI imaging, cognitive, clinical, physical and body composition markers to better understand the mechanisms of cognitive frailty. PERSPECTIVE: COGFRAIL study will give the opportunity to better understand the link between Gerosciences, frailty, cognitive impairment, and Alzheimer's disease, and to better characterize the physical and cognitive trajectories of frail older adults according to their amyloid status. Understanding the relationship between physical frailty and cognitive impairment is a prerequisite for the development of new interventions that could prevent and treat both conditions.

Age effects on the neural processing of object-context associations in briefly flashed natural scenes.

In daily life, fast visual recognition of surrounding objects is facilitated through context-based expectations. However the ability to rapidly and accurately recognize unexpected stimuli in a given environment is also crucial and this ability is impaired with age. The present fMRI study aimed at comparing in young and older adults the neural correlates of fast object processing. Patterns of cerebral activity were investigated in response to briefly-presented (100 ms) congruent and incongruent natural scenes. Participants were slower and less accurate when categorizing objects in incongruent relative to congruent contexts. This behavioral cost was notably more pronounced in the older group. Height and multivariate patterns of fMRI activity in context-selective regions were equivalent in both age groups, suggesting preserved processing of coarse scene features in older participants. Incongruent scenes elicited additional activity in the parahippocampal gyrus that possibly reflected simultaneous activation of rarely co-occurring neural representations. Contextual effects were observed in object-selective cortex for the young group only, and may be driven by detection of mismatch between actually perceived and previously-experienced associations. In the older group exclusively, increased bilateral prefrontal and left fusiform activity in response to incongruent scenes was observed. However this supplemental activity was not found to efficiently contribute to improve task performance in difficult visual conditions. Altogether these results suggest age-related changes in the interaction between object- and context-processing pathways, that may subserve impairment in fast identification of unexpected objects in natural scenes.

Longitudinal changes of tau PET imaging in relation to hypometabolism in prodromal and Alzheimer's disease dementia.

The development of tau-specific positron emission tomography (PET) tracers allows imaging in vivo the regional load of tau pathology in Alzheimer's disease (AD) and other tauopathies. Eighteen patients with baseline investigations enroled in a 17-month follow-up study, including 16 with AD (10 had mild cognitive impairment and a positive amyloid PET scan, that is, prodromal AD, and six had AD dementia) and two with corticobasal syndrome. All patients underwent PET scans with [18F]THK5317 (tau deposition) and [18F]FDG (glucose metabolism) at baseline and follow-up, neuropsychological assessment at baseline and follow-up and a scan with [11C]PIB (amyloid-ß deposition) at baseline only. At a group level, patients with AD (prodromal or dementia) showed unchanged [18F]THK5317 retention over time, in contrast to significant decreases in [18F]FDG uptake in temporoparietal areas. The pattern of changes in [18F]THK5317 retention was heterogeneous across all patients, with qualitative differences both between the two AD groups (prodromal and dementia) and among individual patients. High [18F]THK5317 retention was significantly associated over time with low episodic memory encoding scores, while low [18F]FDG uptake was significantly associated over time with both low global cognition and episodic memory encoding scores. Both patients with corticobasal syndrome had a negative [11C]PIB scan, high [18F]THK5317 retention with a different regional distribution from that in AD, and a homogeneous pattern of increased [18F]THK5317 retention in the basal ganglia over time. These findings highlight the heterogeneous propagation of tau pathology among patients with symptomatic AD, in contrast to the homogeneous changes seen in glucose metabolism, which better tracked clinical progression.

Comparison between PET template-based method and MRI-based method for cortical quantification of florbetapir (AV-45) uptake in vivo.

PURPOSE: Florbetapir (AV-45) has been shown to be a reliable tool for assessing in vivo amyloid load in patients with Alzheimer's disease from the early stages. However, nonspecific white matter binding has been reported in healthy subjects as well as in patients with Alzheimer's disease. To avoid this issue, cortical quantification might increase the reliability of AV-45 PET analyses. In this study, we compared two quantification methods for AV-45 binding, a classical method relying on PET template registration (route 1), and a MRI-based method (route 2) for cortical quantification. METHODS: We recruited 22 patients at the prodromal stage of Alzheimer's disease and 17 matched controls. AV-45 binding was assessed using both methods, and target-to-cerebellum mean global standard uptake values (SUVr) were obtained for each of them, together with SUVr in specific regions of interest. Quantification using the two routes was compared between the clinical groups (intragroup comparison), and between groups for each route (intergroup comparison). Discriminant analysis was performed. RESULTS: In the intragroup comparison, differences in uptake values were observed between route 1 and route 2 in both groups. In the intergroup comparison, AV-45 uptake was higher in patients than controls in all regions of interest using both methods, but the effect size of this difference was larger using route 2. In the discriminant analysis, route 2 showed a higher specificity (94.1 % versus 70.6 %), despite a lower sensitivity (77.3 % versus 86.4 %), and D-prime values were higher for route 2. CONCLUSION: These findings suggest that, although both quantification methods enabled patients at early stages of Alzheimer's disease to be well discriminated from controls, PET template-based quantification seems adequate for clinical use, while the MRI-based cortical quantification method led to greater intergroup differences and may be more suitable for use in current clinical research.

Object recognition in congruent and incongruent natural scenes: a life-span study.

Efficient processing of our complex visual environment is essential and many daily visual tasks rely on accurate and fast object recognition. It is therefore important to evaluate how object recognition performance evolves during the course of adulthood. Surprisingly, this ability has not yet been investigated in the aged population, although several neuroimaging studies have reported altered activity in high-level visual ventral regions when elderly subjects process natural stimuli. In the present study, color photographs of various objects embedded in contextual scenes were used to assess object categorization performance in 97 participants aged from 20 to 91. Objects were either animals or pieces of furniture, embedded in either congruent or incongruent contexts. In every age group, subjects showed reduced categorization performance, both in terms of accuracy and speed, when objects were seen in incongruent vs. congruent contexts. In subjects over 60 years old, object categorization was greatly slowed down when compared to young and middle-aged subjects. Moreover, subjects over 75 years old evidenced a significant decrease in categorization accuracy when objects were seen in incongruent contexts. This indicates that incongruence of the scene may be particularly disturbing in late adulthood, therefore impairing object recognition. Our results suggest that daily visual processing of complex natural environments may be less efficient with age, which might impact performance in everyday visual tasks.

[Early diagnosis of Alzheimer's disease]. / Diagnostic précoce de la maladie d'Alzheimer.

INTRODUCTION: Diagnosis of Alzheimer's disease (AD) remains difficult to establish, and can only be considered as certain thanks to anatomopathological evidence, or genetic mutations. Current diagnostic criteria rely on innovative imaging and biological tools, in order to detect pathological cues from very early stages, and with best sensibility and sensitivity. STATE OF ART: Advances in neuro-imaging enabled the development of different tools to help establishing the diagnosis, such as cerebral atrophy assessment on magnetic resonance imaging (MRI), and cerebral metabolism study on positron emission tomography (PET). Besides, the increasing use of in vivo biological markers, combined to clinical criteria, enables to discriminate patients from healthy controls at even earlier stages. This includes studies on tau and beta-amyloid proteins concentrations in the cerebrosinal fluid, and amyloid-specific radioligands uptake. Familial forms of Alzheimer represent a great model for studying early or even pre-symptomatic AD, as genetic analyses constitute a diagnosis of certainty, even though they usually evolve earlier and faster. PERSPECTIVES, CONCLUSION: Diagnostic tools are more and more numerous and performant. According to patients' clinical heterogeneity, it appears essential to associate different method to investigate, in order to make a diagnosis as early and as reliable as possible.